HK1020951B - Method for producing pyridine derivatives - Google Patents

Description

Process for preparing pyridine derivatives

Technical Field

The present invention relates to a process for the preparation of pyridine derivatives, to intermediates in the synthesis. The pyridine derivatives prepared by the present invention are useful as intermediates in the synthesis of compounds having a pyridine skeleton in the molecule, such as furopyridine derivatives having antiviral activity (see WO 96/35678).

Background

Several methods have been disclosed for the synthesis of fused pyridines such as furopyridines (see Heterocycles, 45(5) (1997), p.975), but only 5-substituted furo [2, 3-c ] pyridines which can be converted into the aforementioned furopyridine derivatives having antiviral activity have been disclosed in a multi-step synthesis using 2-chloro-3-hydroxypyridine as a starting material (see WO96/35678), and 5-substituted furo [2, 3-c ] pyridine N-oxides obtained by cyclization and subsequent dehydrogenation of a furfural oxime as a starting material by Aza Diels-Alder reaction (see Tetrahedron Lett., 32, 3199 (1991)).

However, the former method has problems in that there are too many steps and raw materials and reactants are expensive, and the latter method requires an expensive dehydrogenation agent such as 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) and reduction of pyridine oxide to pyridine, so that both methods cannot be industrially used.

Disclosure of Invention

It is an object of the present invention to provide a process for producing pyridine derivatives which are easy to prepare fused pyridine derivatives such as furopyridine derivatives subsequently, under mild conditions in an industrially useful manner and in good yield.

It is another object of the present invention to provide a synthetic intermediate and a method for preparing the same, which facilitates the preparation of the aforementioned pyridine derivatives in an industrially applicable manner.

These objects have been achieved in the present invention described below.

The invention provides a method for preparing pyridinol derivatives represented by a general formula III

(wherein A represents a divalent organic group which may contain one to three oxygen, nitrogen and/or sulfur atoms, wherein A may form together with the two bonded carbon atoms a 5-, 6-, 7-or 8-membered ring which may form a fused ring with one or more additional rings; R⁵Represents a hydrogen atom, -CHR¹R²Alkenyl, aryl or aralkyl which may be substituted; r¹And R²Each independently represents a hydrogen atom or a hydrocarbon group which may be substituted; and R⁶An alkyl group, an alkenyl group, an aryl group or an aralkyl group) which may be substituted, which comprises:

pyridine ester derivatives represented by the general formula I-1

(wherein Z is¹represents-COX; x represents an alkoxy group, an alkenyloxy group, an aryloxy group or an aralkyloxy group which may be substituted; and A is as defined above)

Reacting with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent to give a pyridine carbonyl derivative represented by the general formula II

(wherein A and R⁵As defined above); and

reacting the obtained pyridine carbonyl derivative represented by the general formula II with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent to obtain a pyridinol derivative of the general formula III.

The present invention also provides a process for producing a pyridinol derivative represented by the general formula III, which comprises:

reacting the pyridine carbonyl derivative represented by the general formula II with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent, or an aralkylating agent to obtain a pyridinol derivative of the formula III.

The present invention further provides a pyridine carbonyl derivative represented by the general formula II-1

(wherein R is⁵Represents a hydrogen atom, -CHR¹R²Alkenyl, aryl or aralkyl which may be substituted; r¹And R²Each independently represents a hydrogen atom or a hydrocarbon group which may be substituted; q represents a divalent group selected from-ND-, -O-, and-S-; and D represents a hydrogen atom or a hydrocarbon group which may be substituted).

The present invention still further provides a method for preparing a pyridine carbonyl derivative represented by the general formula II, which comprises:

a pyridine ester derivative represented by the general formula I-1 is reacted with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent.

The present invention still further provides a process for producing a pyridinol derivative represented by the general formula III, which comprises:

reacting a pyridine ester derivative represented by the general formula I-1 with an ester compound represented by the general formula IV in the presence of a base

R¹R²CHCO₂R³ (IV)

(wherein R is¹And R²As defined above; and R is³Is a hydrocarbon group which may be substituted) to give a pyridine beta-keto ester derivative represented by the general formula V

(wherein R is¹And R²And A is as defined above; and R is⁴Is a hydrocarbon group which may be substituted); and

hydrolyzing and decarboxylating the obtained pyridine beta-keto ester derivative represented by the general formula V to obtain a pyridine carbonyl derivative represented by the general formula II; and

reacting the pyridine carbonyl derivative represented by the general formula II with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent to obtain a pyridinol derivative represented by the general formula III.

The present invention further provides a process for the preparation of a pyridine β -keto ester derivative represented by the general formula V, which comprises:

the pyridine ester derivative represented by the general formula I-1 is reacted with the ester compound represented by the general formula IV in the presence of a base to obtain a pyridine beta-keto ester derivative represented by the general formula V.

The present invention still further provides a pyridine beta-keto ester derivative represented by the general formula V-1

(wherein R is¹And R²Each independently represents a hydrogen atom or a hydrocarbon group which may be substituted;R⁴represents a hydrocarbon group which may be substituted; q represents a divalent group selected from-ND-, -O-, and-S-; and D represents a hydrogen atom or a hydrocarbon group which may be substituted).

The present invention also provides a method for preparing a pyridine carbonyl derivative represented by the general formula II, which comprises:

the pyridine beta-keto ester derivative represented by the general formula V is hydrolyzed and decarboxylated to give a pyridine carbonyl derivative represented by the general formula II.

The invention also provides a pyridine ester derivative represented by the general formula I-1

(wherein Z is¹represents-COX; and X represents an alkoxy group, an alkenyloxy group, an aryloxy group or an aralkyloxy group which may be substituted).

The present invention also provides sulfonylpyridine derivatives represented by the general formula I-2

(wherein Z is²represents-SO₂R⁹An organic sulfonyl group shown; r⁹Represents an organic group; and A represents a divalent organic group which may contain one to three oxygen, nitrogen and/or sulfur atoms, wherein A may form a 5-, 6-, 7-, or 8-membered ring together with the two bonded carbon atoms, and the ring may form a fused ring with one or more additional rings).

The invention also provides a preparation method of the pyridine derivative shown in the general formula I

(wherein Z isⁿN of (1) is 1 or 2; z¹represents-COX(ii) a X represents an alkoxy group, an alkenyloxy group, an aryloxy group or an aralkyloxy group which may be substituted; z²Is represented by the formula-SO₂R⁹An organic sulfonyl group shown; r⁹Is an organic group; and A represents a divalent organic group which may contain one to three oxygen, nitrogen and/or sulfur atoms, wherein A may form together with the two bonded carbon atoms a 5-, 6-, 7-, or 8-membered ring which may form a fused ring with one or more additional rings), wherein the process comprises:

reacting an imine derivative represented by the formula VI

(wherein R is⁷Is an alkyl, alkenyl, aryl or aralkyl group which may be substituted; and A is as defined above) with a carbonylating agent of the formula VII

(wherein R is⁸Is a hydrogen atom or an alkyl, alkenyl, aryl, aralkyl, alkoxy, alkenyloxy, aryloxy, aralkyloxy or amino group which may be substituted; and Y represents a leaving group) and a nitrile derivative represented by the general formula VIII

ZⁿCN (VIII)

(wherein Z isⁿAs defined above)

Reacting to obtain the pyridine derivative shown in the general formula I.

The imine derivative represented by the formula VI can be obtained preferably by the following method:

reacting an aldehyde derivative represented by the formula IX

(wherein A is as defined above)

With primary amines of the formula X

R⁷NH₂ (X)

(wherein R is⁷As defined above)

The imine derivative represented by the general formula VI is obtained.

These and other objects, features and advantages of the present invention will be described or illustrated in the following detailed description of the invention.

The present invention can be understood in more detail by reference to the following reaction schemes.

Reaction scheme

First, the substituents used in the general formula of the reaction scheme are explained as follows.

Specific examples of the ring formed by a together with the two bonded carbon atoms in the above general formula include 5-membered rings such as dihydrofuran ring, furan ring, pyrrole ring, pyrroline ring, dehydrodioxolane, pyrazole ring, pyrazoline ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, oxadiazole ring, and triazole ring; 6-membered rings such as a pyran ring, a dihydropyran ring, a pyridine ring, a dihydropyridine ring, a tetrahydropyridine ring, a dehydrodioxane ring, a dehydromorpholine ring, a pyridazine ring, a dihydropyridazine ring, a pyrimidine ring, a dihydropyrimidine ring, a tetrahydropyrimidine ring, a pyrazine ring, and a dihydropyrazine ring; various aza-, oxa-and thia-substituted derivatives of 7-membered rings such as thiaza * ring and cycloheptene ring, cycloheptadiene ring and cycloheptatriene ring; and various aza-, oxa-or thia-substituted derivatives of 8-membered rings such as cyclooctene ring, cyclooctadiene ring and cyclooctatetraene ring.

When a ring formed with two bonded carbon atoms forms a fused ring with one or more other rings, specific examples of the fused ring include a benzofuran ring, an isobenzofuran ring, a benzopyran ring, a indolizine ring, an indole ring, an isoindole ring, a quinolizine ring, an indazole ring, an isoquinoline ring, a 2, 3-naphthyridine ring, a naphthyylidine ring, a quinoxaline ring, a benzothiophene ring, and hydrogenated forms thereof. Any of the above rings may be substituted.

X or R⁸Examples of the alkoxy group represented include straight or branched alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy and octyloxy; and cycloalkoxy groups such as cyclopropoxy, cyclopentoxy, and cyclohexyloxy. These alkoxy groups and cycloalkoxy groups may be substituted, and examples of the substituent include halogen atoms such as chlorine, bromine, iodine and fluorine; alkoxy groups such as methoxy, ethoxy, propoxy and butoxy; a hydroxyl group; a nitro group; and aryl groups such as phenyl, p-methoxyphenyl, and p-chlorophenyl.

By X or R⁸Examples of the alkenyloxy group represented include propenyloxy, butenyloxy and octenyloxy; examples of the aryloxy group include a phenoxy group; examples of the aralkyloxy group include benzyloxy groups. These alkenyloxy, aryloxy and aralkyloxy groups may be substituted, and examples of the substituent include halogen atoms such as chlorine, bromine, iodine and fluorine; alkoxy groups such as methoxy, ethoxy, propoxy and butoxy; a hydroxyl group; alkyl groups such as methyl, ethyl, propyl and butyl; trisubstituted siloxy groups such as t-butyldimethylsilyloxy and t-butyldiphenylsiloxy; a nitro group; and aryl groups such as phenyl, p-methoxyphenyl, and p-chlorophenyl.

From R⁹Examples of the organic group represented include alkyl groups such as methyl, ethyl, propyl, tert-butyl, octyl and dodecyl; aryl groups such as phenyl, tolyl, chlorophenyl, nitrophenyl and naphthyl; and aralkyl groups such as benzyl and nitrobenzyl.

From R¹，R²，R³，R⁴Examples of the hydrocarbon group represented by D include alkyl groups, alkenyl groups, aryl groups and aralkyl groups. Examples of alkyl groups includeStraight-chain or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl; and cycloalkyl groups such as cyclopropyl, cyclopentyl and cyclohexyl. These alkyl groups may be substituted, and examples of the substituent include halogen atoms such as chlorine, bromine, iodine and fluorine; alkoxy groups such as methoxy, ethoxy, propoxy and butoxy; a hydroxyl group; trisubstituted siloxy groups such as t-butyldimethylsilyloxy and t-butyldiphenylsiloxy; a nitro group; and aryl groups such as phenyl, p-methoxyphenyl, and p-chlorophenyl.

Examples of alkenyl groups include ethenyl, propenyl, butenyl and octenyl; examples of aryl groups include phenyl; and examples of the aralkyl group include benzyl. These alkenyl, aryl, and aralkyl groups may be substituted, and examples of such substituents include halogen atoms such as chlorine, bromine, iodine, and fluorine; alkoxy groups such as methoxy, ethoxy, propoxy and butoxy; a hydroxyl group; alkyl groups such as methyl, ethyl, propyl and butyl; trisubstituted siloxy groups such as t-butyldimethylsilyloxy and t-butyldiphenylsiloxy; a nitro group; and aryl groups such as phenyl, p-methoxyphenyl, and p-chlorophenyl.

From R⁵，R⁶，R⁷And R⁸Examples of the alkyl group represented include straight-chain or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl; and cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

These alkyl groups may be substituted, and examples of the substituent include halogen atoms such as chlorine, bromine, iodine and fluorine; a hydroxyl group; alkoxy groups such as methoxy, ethoxy, propoxy and butoxy; trisubstituted siloxy groups such as t-butyldimethylsilyloxy and t-butyldiphenylsiloxy; a nitro group; and aryl groups such as phenyl, p-methoxyphenyl, and p-chlorophenyl.

From R⁵，R⁶，R⁷And R⁸Examples of the alkenyl groupsExamples include ethenyl, propenyl, butenyl and octenyl; examples of aryl groups include phenyl and naphthyl; and examples of the aralkyl group include benzyl. Thus, the alkenyl group, the aryl group and the aralkyl group may be substituted, and examples of the substituent include halogen atoms such as chlorine, bromine, iodine and fluorine; a hydroxyl group; alkyl groups such as methyl, ethyl, propyl and butyl; alkoxy groups such as methoxy, ethoxy, propoxy and butoxy; trisubstituted siloxy groups such as t-butyldimethylsilyloxy and t-butyldiphenylsiloxy; a nitro group; and aryl groups such as phenyl, p-methoxyphenyl, and p-chlorophenyl.

From R⁸Examples of the substitutable amino group include C₁To C₈Straight-chain or branched amino groups such as amino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, dihexylamino and dioctylamino.

These amino groups may be substituted, and the substituents include halogen atoms such as chlorine, bromine, iodine or fluorine; a hydroxyl group; alkoxy groups such as methoxy, ethoxy, propoxy or butoxy; trisubstituted siloxy groups such as t-butyldimethylsilyloxy and t-butyldiphenylsiloxy; a nitro group; and phenyl, p-methoxyphenyl, and p-chlorophenyl.

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

The production process of the present invention will be described in detail in terms of the respective steps.

Step (a): a step of preparing an imine derivative VI by dehydrating condensation of an aldehyde derivative IX and a primary amine X.

The conversion can be carried out in the same manner as in a method commonly used for obtaining imine compounds from aldehydes and primary amines. For example, the aldehyde derivative IX is mixed with the primary amine X in the presence or absence of a solvent, in the presence or absence of a dehydrating agent. Suitable solvents should not adversely affect the reaction and include aliphatic hydrocarbon solvents such as pentane, hexane, heptane and petroleum spirit; aromatic hydrocarbon solvents such as benzene, toluene, xylene and chlorobenzene; ether solvents such as diethyl ether, tetrahydrofuran and dioxane; alcohol solvents such as methanol and ethanol; ester solvents such as methyl acetate, ethyl acetate and butyl acetate; or mixtures thereof. Suitable dehydrating agents include silica gel, molecular sieves, alumina, sodium sulfate, magnesium sulfate, copper sulfate, sodium hydroxide, or potassium hydroxide. When water is removed by azeotropic dehydration reaction, the reaction can also be carried out in an azeotropic solvent with water.

Examples of the primary amine X include methylamine, ethylamine, propylamine, n-butylamine, n-hexylamine, n-octylamine, aniline, p-chloroaniline, p-methoxyaniline, p-toluidine and p-nitroaniline.

The resulting imine derivative IV can be isolated and purified from the reaction mixture in accordance with the general procedures conventionally used for the isolation and purification of organic compounds. For example, insoluble matter contained in the reaction mixture can be separated by filtration, and the filtrate can be concentrated and the residue can be purified by recrystallization, chromatography, or the like to obtain the imine derivative VI. The crude product can also be used without purification for the subsequent reaction. When the imine derivative VI precipitates from the reaction mixture, it is filtered and, if necessary, purified by recrystallization and then available for subsequent reaction.

Step (b): step of preparing pyridine derivative I by reacting imine derivative VI with carbonylation agent VII and nitrile VIII

Examples of the carbonylating agent VII include carboxylic anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride and trifluoroacetic anhydride; acyl halides such as acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, benzoyl chloride and benzoyl bromide; haloformates such as methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, allyl chloroformate, phenyl chloroformate, nitrophenyl chloroformate and benzyl chloroformate; and carbamoyl halides such as N, N-dimethylcarbamoyl chloride; among them, chloroformates are preferred.

The amount of the carbonylating agent VII used is preferably in the range of 0.5 to 20mol, more preferably 1.1 to 10mol, based on one mol of the imine derivative VI.

Examples of the nitrile VIII include alkylsulfonyl cyanides such as methylsulfonyl cyanide, ethylsulfonyl cyanide, propylsulfonyl cyanide, butylsulfonyl cyanide, t-butylsulfonyl cyanide, and dodecylsulfonyl cyanide; arylsulfonyl cyanides such as benzenesulfonyl cyanide, toluenesulfonyl cyanide, chlorobenzenesulfonyl cyanide, nitrobenzenesulfonyl cyanide and naphthalenesulfonyl cyanide; aralkyl sulfonyl cyanides such as benzyl sulfonyl cyanide and nitrobenzyl sulfonyl cyanide; cyanoformates such as methyl cyanoformate, ethyl cyanoformate, propyl cyanoformate, isopropyl cyanoformate, butyl cyanoformate, allyl cyanoformate, phenyl cyanoformate, nitrophenylcyanoformate and benzyl cyanoformate. The amount of the nitrile VIII used is preferably in the range of 0.5 to 20mol, more preferably 1.1 to 10mol, based on one mol of the imine derivative VI.

The reaction may 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, and examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene, * and chlorobenzene; ethers such as tetracyanofuran and dioxane; amides such as dimethylformamide and 1-methyl-2-pyrrolidone; and dimethyl sulfoxide. The amount of the solvent is not particularly limited, although a range of 1 to 200 times by weight of the imine derivative VI is generally preferred.

The reaction temperature varies depending on the solvent, the carbonylating agent VII used, and the nitrile VIII, and preferably ranges from 40 ℃ to the reflux temperature of the reaction system. The reaction may be carried out under increased pressure or reduced pressure. The reaction time varies depending on the reaction temperature and generally ranges from 30 minutes to 24 hours. The reaction time can be controlled by appropriately controlling the reaction temperature.

For example, the reaction can be carried out in the following manner. That is, the carbonylating agent VII is dropped into a mixed solution of the nitrile VIII and the imine derivative VI at a temperature from ice-cooling to the reflux temperature of the reaction mixture, and after the dropping, the mixture is heated to a desired temperature until the imine derivative VI disappears.

The pyridine derivative I obtained can be isolated and purified from the reaction mixture in accordance with the general procedures conventionally used for the isolation and purification of organic compounds. For example, after the reaction mixture is cooled to room temperature, it is washed with an aqueous sodium bicarbonate solution and brine. Then, the solvent is evaporated, and the residue is purified by recrystallization, chromatography, or the like. When the product precipitates from the reaction mixture, the reaction mixture may be cooled, a poor solvent may be added if necessary, and then filtered.

Step (C): a step of producing a pyridine carbonyl derivative II by reacting a pyridine ester derivative I-1 with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent.

Examples of the reducing agent include metal borohydrides such as sodium borohydride and lithium borohydride; and metal aluminum hydrides such as diisobutylaluminum hydride, lithium aluminum hydride and sodium bismethoxyethoxyaluminum hydride. Examples of the alkylating agent include alkylmetal compounds such as methyllithium, n-butyllithium, methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride and methylcerium chloride; examples of the alkenylating agent 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 phenyl lithium and phenyl magnesium bromide; and examples of the aralkylating agent include aralkyl metal compounds such as benzyl lithium and benzyl magnesium bromide. The amount of the reducing agent, alkylating agent, alkenylating agent, arylating agent and aralkylating agent to be used is preferably in the range of 0.5 to 20mol, more preferably 1.1 to 2.0mol, based on one mole of the pyridine ester derivative I-1.

The reaction can be carried out with or without a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples include ethers such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, 1, 2-diethoxyethane and diethylene glycol dimethyl ether; hydrocarbons such as hexane, benzene, toluene, xylene, * and chlorobenzene; and amides such as 1-methyl-2-pyrrolidone. The amount of the solvent is not particularly limited, although it is usually used in a preferred range of 1 to 200 times by weight based on the weight of the pyridine ester derivative I-1.

The reaction temperature may vary depending on the solvent, reducing agent, alkylating agent, alkenylating agent, arylating agent or aralkylating agent used, but it is generally preferred to range from-100 ℃ to the reflux temperature of the solvent. The reaction may be carried out under increased pressure or reduced pressure. The reaction time may also vary depending on the reaction temperature, but is generally 30 minutes to 24 hours. The reaction time can be controlled by appropriately controlling the reaction temperature.

The obtained pyridine carbonyl derivative II can be isolated and purified from the reaction mixture in the usual manner commonly used for the isolation and purification of organic compounds. For example, after the reaction mixture is returned to room temperature, an acidic aqueous solution such as an aqueous ammonium chloride solution is added thereto and hydrolyzed, followed by extraction with an organic solvent such as diethyl ether or ethyl acetate, the extract is washed with an aqueous sodium bicarbonate solution and brine, the solvent is distilled off, and the residue is purified by distillation, recrystallization, chromatography or the like.

Using a reducing agent with hydrogen as nucleophilic agent, metal borohydrides such as sodium borohydride, lithium borohydride; and metal aluminum hydrides such as lithium aluminum hydride, sodium bis (methoxyethoxy) aluminum hydride, in which R is obtained by a one-step reaction⁵And R⁶A pyridinol derivative III which is a hydrogen atom.

Step (d): a step of producing a pyridinol derivative III by reacting a pyridylcarbonyl derivative II with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent.

Examples of the reducing agent include metal borohydrides such as sodium borohydride and lithium borohydride and metal aluminum hydrides such as diisobutylaluminum hydride, lithium aluminum hydride, and sodium bismethoxyethoxyaluminum hydride. The reduction reaction may also be carried out using hydrogen and a metal catalyst such as Raney nickel or Raney cobalt. Reduction can also be carried out using aluminum isopropoxide in isopropanol. The amount of the reducing agent to be used is preferably in the range of 1.0 to 20mol, more preferably 1.1 to 5mol, based on one mol of the pyridine carbonyl derivative II.

Examples of the alkylating agent include alkylmetal compounds such as methyllithium, n-butyllithium, methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, and methylcerium chloride; examples of the alkenylating agent 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 phenyl lithium and phenyl magnesium bromide; and examples of the aralkylating agent include aralkyl metal compounds such as benzyl lithium and benzyl magnesium bromide. The amount of the alkylating agent, alkenylating agent, arylating agent or aralkylating agent to be used is preferably in the range of 0.5 to 20mol, more preferably 1.1 to 2.0mol, based on one mole of the pyridine carbonyl derivative II, the alkylating agent, the alkenylating agent, the arylating agent or the aralkylating agent.

The reaction can be carried out with or without a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent include alcohols such as methanol, ethanol, propanol and isopropanol; ethers such as diethyl ether, diisopropyl ether, 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 is not particularly limited, but is preferably in the range of 1 to 200 times by weight of the pyridine carbonyl derivative II.

The reaction temperature may vary depending on the solvent, reducing agent, alkylating agent, alkenylating agent, arylating agent, or aralkylating agent used, but the preferred temperature range is from-100 ℃ to the reflux temperature of the solvent. The reaction may be carried out under increased or reduced pressure. The reaction time may also vary depending on the reaction temperature, but is usually 30 minutes to 24 hours. The reaction time can be controlled by appropriately controlling the reaction temperature.

The resulting pyridinol derivative III can be isolated and purified from the reaction mixture in accordance with the general methods conventionally used for the isolation and purification of organic compounds. For example, after the reaction mixture is returned to room temperature, an acidic aqueous solution such as an aqueous ammonium chloride solution is added thereto and hydrolyzed, followed by extraction with an organic solvent such as diethyl ether or ethyl acetate, the extract is washed with an aqueous sodium bicarbonate solution and brine, the solvent is distilled off, and the residue is purified by distillation, recrystallization, chromatography or the like.

A step (e): a step of producing a pyridine β -keto ester derivative V by reacting a pyridine ester derivative I-1 with an ester compound IV 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; metal alkoxides such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide, sodium tert-butoxide, sodium benzylmethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium butoxide and potassium tert-butoxide; organomagnesium halides such as methylmagnesium bromide, ethylmagnesium bromide, isopropylmagnesium bromide, and * -ylmagnesium bromide; metal hydrides such as sodium hydride and potassium hydride; and metal amides such as sodium amide, potassium amide, and lithium diisopropylamide. The amount of the base to be used is preferably in the range of 0.5 to 10mol, more preferably 1 to 3mol, based on one mol of the pyridine ester derivative I-1.

The ester compound IV is an ester compound derived from a carboxylic acid having a hydrogen atom at the α -position, preferably an ester compound of a carboxylic acid such as acetic acid, propionic acid, butyric acid, isobutyric acid, 2-methylpropionic acid, valeric acid, isovaleric acid, hexanoic acid, or phenylacetic acid, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, 2-methylpropyl ester, tert-butyl ester, phenyl ester, benzyl ester, or chlorophenyl ester. Among them, esters of aliphatic lower alcohols such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, 2-methylpropyl ester and tert-butyl ester are preferable.

The ester compound IV is preferably used in an amount ranging from 0.5 to 10mol, more preferably from 1 to 3mol, based on one mol of the pyridine ester derivative I-1.

Although the step reaction may be carried out without a solvent, it 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, and examples of the solvent include aliphatic hydrocarbons such as pentane, hexane, cyclohexane, octane and petroleum jelly; aromatic hydrocarbons such as benzene, toluene, xylene, cumene and *; ethers such as diethyl 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; and alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol. Among them, in view of the reaction rate, solubility of the pyridine derivative I, etc., aromatic hydrocarbons, ethers and polyethers are preferably used as the solvent. The amount of the solvent is not particularly limited as long as the pyridine ester derivative I-1 is soluble under the reaction conditions, but it is preferable to use 0.5 to 1000 times, more preferably 0.5 to 100 times the weight of the pyridine ester derivative I-1.

The reaction temperature is preferably in the range of 0 to 200 deg.C, more preferably 10 to 150 deg.C.

The reaction of this step is not limited to any particular method, and examples that may be included are: (1) mixing the specified amount of pyridine ester derivative I-1, base, ester compound IV and solvent, and reacting the mixture at a specified temperature; (2) dissolving a prescribed amount of pyridine ester derivative I-1 in a solvent, adding a base to the solution, heating the solution to a desired temperature, and then adding ester compound IV itself or an ester compound dissolved in a solvent all at once, intermittently or continuously; and (3) dissolving a prescribed amount of a base in a solvent, adding ester compound IV to the solution, heating the solution to a desired temperature, and then adding pyridine ester derivative I-1 itself or pyridine ester derivative I-1 dissolved in a solvent all at once, intermittently or continuously to start the reaction.

The obtained pyridine β -keto ester derivative V can be conveniently isolated by neutralizing the reaction solution by adding an acid equivalent to the base used, then extracting the product with methylene chloride, toluene, xylene, benzene, chloroform, pentane, hexane, heptane or the like, and concentrating the extract. Examples of acids which can be used for this purpose include carboxylic acids such as acetic acid and formic acid, and inorganic acids such as hydrochloric acid and sulfuric acid. The purity of the product can be improved by recrystallization if desired.

Under these reaction conditions, depending on the combination of the pyridine ester derivative I-1, the base, and the ester compound IV, and the ratio in which they are used, particularly when a metal alkoxide is used as the base or an alcohol is used as the solvent, sometimes-X in the pyridine ester derivative I-1 representsA group of (A), an ester compound IV of-OR³The group represented, the alcohol portion of the metal alkoxide and the alcohol may undergo a transesterification reaction. In this case the product would become-OR in the pyridine beta-keto ester derivative V⁴Mixtures of various types of moieties are indicated, but the purity of the mixture may be conveniently enhanced by conventional means of separation and purification such as distillation, column chromatography, and recrystallization. These mixtures can also be used without problems in the following step (f) for the preparation of the pyridine carbonyl derivative II.

Step (f): a step of preparing a pyridine carbonyl derivative II by hydrolyzing and decarboxylating the pyridine β -keto ester derivative V.

The amount of water used in the hydrolysis is not particularly limited, but in order to obtain the objective pyridine carbonyl derivative II in a high yield, at least one mole of water is used per mole of the pyridine β -keto ester derivative V, and in order to secure the reaction rate, the extraction efficiency after the reaction, the volume efficiency of the apparatus, and the like, it is preferable to use not more than 100 moles of water per mole of the pyridine β -keto ester derivative V.

Any acid or base commonly used in ester hydrolysis may be used for the hydrolysis reaction. Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and acidic gases such as hydrogen chloride can also be used. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide.

The intermediate product obtained by hydrolysis of the pyridine β -keto ester derivative V under the above reaction conditions is unstable, and decarboxylation proceeds rapidly, resulting in the pyridine carbonyl derivative II, and therefore, decarboxylation is carried out simultaneously with hydrolysis in the same reactor using the same acid or base used for hydrolysis. More acid or base may be added to promote the hydrolysis and decarboxylation reactions during the reaction. The type of acid or base added at this time may be the same as or different from the acid or base originally used for hydrolysis and decarboxylation. The amount of the acid or the base to be used is preferably in the range of 0.001 to 100mol, more preferably 0.01 to 10mol, based on one mol of the pyridine β -keto ester derivative V.

The method of carrying out the reaction comprises: firstly, starting hydrolysis and decarboxylation under an alkaline condition, and adding excessive acid into a reaction system in the middle of the reaction process to change the reaction system into an acidic condition; and firstly, starting hydrolysis and decarboxylation under an acidic condition, and adding excessive alkali into a reaction system in the middle of the reaction process to enable the reaction system to be under an alkaline condition.

In order to obtain a pyridinecarbonyl derivative II, the reaction in step (e) is carried out to obtain a reaction mixture containing a pyridinebeta-keto ester derivative V, and the pyridinebeta-keto ester derivative V is not separated from the reaction mixture, and water and an acid or a base are added to the reaction solution to carry out the hydrolysis and decarbonylation in step (f) to obtain a pyridinecarbonyl derivative II.

When the hydrolysis and decarboxylation in step (f) are carried out without separating the pyridine β -keto ester derivative V from the reaction mixture obtained in the reaction in step (e), the pyridine β -keto ester derivative V contained in the reaction mixture is quantified and analyzed, and the amount of the acid or base used should be within the above range relative to the amount. The amount of the acid or the base to be used is preferably in the range of 0.001 to 100mol, more preferably 0.01 to 10mol, per mol of the pyridine ester derivative I-1 used in step (e). The amount of water used is preferably in the range of 1 to 100mol based on the amount of the pyridine β -keto ester derivative V contained in the reaction mixture. The amount of water used may also preferably range from 1 to 100mol based on one mol of the pyridine ester derivative I-1.

Since the base is already present in the reaction mixture containing the pyridine β -keto ester derivative V obtained in step (e), the addition of water makes the already present base an accelerator for hydrolysis and decarboxylation. In this embodiment, the neutralization in step (e) may be omitted.

The hydrolysis and decarboxylation may be carried out 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 petroleum jelly; aromatic hydrocarbons such as benzene, toluene, xylene, cumene and *; ethers such as diethyl 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; and alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol. Among them, the use of aromatic hydrocarbons, ethers and polyethers is advantageous in terms of reaction speed, solubility of the pyridine β -keto ester derivative V, and the like. The amount of the solvent is not particularly limited, but is preferably in the range of 0.5 to 100 parts by weight based on the pyridine β -keto ester derivative V or the pyridine ester derivative I-1.

When the hydrolysis and decarboxylation of step (f) are carried out without isolating the pyridine β -keto ester derivative V from the reaction mixture obtained in the reaction of step (e), the solvent used in step (e) can be used in step (f).

The reaction temperature is preferably in the range of 0 to 200 deg.C, more preferably 10 to 150 deg.C.

The obtained pyridine carbonyl derivative II can be isolated and purified from the reaction mixture in a general method commonly used for the isolation and purification of organic compounds. For example, after cooling the reaction mixture to room temperature, extraction is performed with an organic solvent such as dichloromethane, toluene, xylene, benzene, chloroform, pentane, hexane or heptane, the extract is washed with brine, the solvent is distilled off, and the residue is purified by distillation, recrystallization, chromatography and the like.

The obtained pyridine carbonyl derivative II can be converted into the corresponding pyridinol derivative III using the process of step (d).

The pyridine derivatives represented by the general formula I-2 contained in the pyridine derivative I, for example, 5-benzenesulfonylfuro [2, 3-c ] pyridine, can be converted into intermediates described in the unexamined International patent application WO96/35678, according to the following method, and a compound having antiviral activity can be derived using the method described in the application.

That is, 5-benzenesulfonylfuro [2, 3-c ] pyridine is converted to 5-cyanofuro [2, 3-c ] pyridine by reacting it with an alkali metal cyanide. Cyanation can be carried out with or without a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include polar solvents such as dimethylformamide, dimethylsulfoxide, 1, 3-dimethyl-2-imidazolidinone. The reaction can also be carried out as a two-phase reaction using a phase transfer catalyst. The reaction is carried out by heating 5-benzenesulfonylfuro [2, 3-c ] pyridine and an excess of alkali metal cyanide at a temperature ranging from room temperature to reflux temperature. The resulting 5-cyanofuro [2, 3-c ] pyridine may be converted to 5-acetylfuro [2, 3-c ] pyridine by reaction with a methylating agent such as methyllithium or methylmagnesium chloride. The amount of the methylating agent used is preferably in the range of 0.8 to 2mol based on the starting pyridine derivative.

5-acetyl furo [2, 3-c ] pyridines can be synthesized by reacting an acetyl anion equivalent with 5-benzenesulfonyl furo [2, 3-c ] pyridine followed by deprotection. Conventional acetyl anion equivalents may be used, but 2-hydroxypropionitrile cyanohydrin ether is preferred, as well as acetyl anion equivalents prepared from acetaldehyde thioacetal, thioacetal monooxide, and the like, with a strong base such as butyl lithium, t-butyl lithium, methyl lithium, phenyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide (lithium hexamethyldisilazide) or sodium hexamethyldisilazide. The amount of the acetyl anion equivalent to be used is preferably in the range of 0.8 to 2mol per mol of the raw pyridine derivative.

The reaction may be carried out in a solvent having no adverse effect thereon, and preferable examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane and dioxane. The preferred range of reaction temperature is-40 ℃ to 100 ℃.

The resulting product is then worked up and deprotected by conventional means, and the resulting 5-acetylfuro [2, 3-c ] pyridine is converted into an intermediate by reduction with sodium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, etc., as described in unexamined International patent application WO 96/35678.

Detailed Description

Examples

The present invention will be described in further detail below with reference to examples. These examples are not intended to limit the invention in any way.

Example 1

3-Methylfuran-2-carbaldehyde (14.8g, 0.135mol) was mixed with hexane (50mL), aniline (15.1g, 0.162mol) was added over 30 minutes at room temperature, and the mixture was heated under reflux with stirring for 4 hours. The mixture was cooled to room temperature, and then the solvent was distilled off to obtain 28.1g of a crude product, 3-methylfuran-2-carbaldehyde-N-phenylimine.

Benzenesulfonyl cyanide (90.2g, 0.540mol) and ethyl chloroformate (29.3g, 0.270mol) were mixed in xylene (125mL) at room temperature and stirred to reflux at a temperature of 120 to 140 ℃. A solution of crude 3-methylfuran-2-carbaldehyde-N-phenylimine (28.1g) obtained in the above reaction in xylene (75mL) was added dropwise to the mixture over 2 hours. After all the solution was added, the reaction mixture was heated under reflux for 3 hours, then cooled to room temperature, and the solvent was distilled off to obtain 81.3g of a crude product. The product was subjected to silica gel column chromatography to give 17.2g of 5-benzenesulfonylfuro [2, 3-c ] pyridine.

¹H-NMR Spectroscopy (270MHz, CDCl)₃，TMS，ppm)δ：6.99(1H，dd，J＝2.16Hz，0.81Hz)，7.49 to 7.62(3H，m)，7.91(1H，d，J＝2.16Hz)，8.07 to 8.11(2H，m)，8.56(1H，d，J＝0.81Hz)，8.90(1H，s).

As shown in example 1, the present invention can provide a method for producing a pyridine derivative useful as an intermediate for antiviral agents and the like under mild conditions in a high yield in a manner suitable for industrial production.

Example 2

Ethyl cyanoformate (21.4g, 0.216mol) and 3-methylfuran-2-carbaldehyde-N-benzimide (10.0g, 54.1mmol) were mixed in xylene (50mL) at room temperature, followed by heating to reflux at 120 to 140 ℃ with stirring. To the resulting solution was added dropwise over an hour a solution of 11.7g (0.108mol) of ethyl chloroformate in xylene (30 mL). After all the solution was added, the reaction mixture was heated under reflux for 2 hours, then cooled to room temperature, and the solvent was distilled off to obtain 14.0g of a crude product. This product was purified by silica gel column chromatography to give 5.40g (yield 52.3%) of 5-ethoxycarbonylfuro [2, 3-c ] pyridine.

¹H-NMR Spectroscopy (270MHz, CDCl)₃，TMS，ppm)δ：1.47(3H，25t，J＝7.16Hz)，4.51(2H，q，J＝7.16Hz)，6.94(1H，dd，J＝2.70Hz，1.08Hz)，7.85(1H，d，J＝2.70Hz)，8.50(1H，d，J＝1.08Hz)，8.99(1H，s).

Example 3

N-butyl cyanoformate (13.7g, 0.108mol) and 3-methylfuran-2-carbaldehyde-N-phenylimine (5.0g, 27.0mmol) were combined in xylene (25mL) at room temperature, then heated to reflux with stirring at 120 to 140 ℃. To the resulting mixture was added dropwise a solution of 7.40g (54.2mol) of n-butyl chloroformate in xylene (15mL) over one hour. After the entire solution was added, the reaction mixture was heated to reflux for 2 hours. Then, it was cooled to room temperature, and the solvent was distilled off to obtain 7.10g of a crude product. The product was purified by silica gel column chromatography to give 2.71g (yield 45.8%) of 5-n-butoxycarbonylfuro [2, 3-c ] pyridine.

¹H-NMR Spectroscopy (270MHz, CDCl)₃，TMS，ppm)δ：0.99(3H，t，J＝7.43Hz)，1.49(2H，tq，J＝7.43Hz)，1.84(2H，tt，J＝7.43 Hz)，4.45(2H，t，J＝7.43Hz)，6.94(1H，dd，J＝2.43Hz，J＝0.81Hz)，7.85(1H，d，J＝2.43Hz)，8.48(1H，d，J＝0.81Hz)，8.99(1H，s).

Example 4

5-Ethoxycarbonylfuro [2, 3-c ] pyridine obtained in example 2 (3.82g, 20.0mmol) was dissolved in tetrahydrofuran (50mL) and cooled to-30 deg.C, to the cooled solution, 22.0mL (22.0mol) of 1.0M methyllithium/diethyl ether solution was added and the solution was stirred at the same temperature for 2 hours, then the reaction mixture was poured into 100mL of 5% aqueous ammonium chloride solution which had been cooled on ice, and the product was extracted twice with 100mL of ethyl acetate. The extract was washed with 100mL of a saturated aqueous sodium bicarbonate solution and 100mL of saturated brine, and then concentrated to obtain 3.12g of a crude product. The product was purified by silica gel column chromatography to give 2.48g (yield 77.0%) of 5-acetylfuro [2, 3-c ] pyridine.

¹H-NMR Spectroscopy (270MHz, CDCl)₃，TMS，ppm)δ：2.79(3H，s)，6.94(1H，dd，J＝2.16Hz，J＝1.08Hz)，7.83(1H，d，J＝2.16Hz)，8.39(1H，d，J＝1.08Hz)，8.91(1H，s).

Example 5

5-Acetylfuro [2, 3-c ] pyridine obtained in example 4 (2.42g, 15.0mmol) was dissolved in toluene (30mL), and the solution was cooled to 0 ℃. To the cooled solution was added 16.0mL (16.0mmol) of a 1.0M toluene solution of diisobutylaluminum hydride, and the solution was stirred at the same temperature for 2 hours. The reaction mixture was then poured into 100mL of 5% aqueous ammonium chloride solution which had been cooled on ice. And extracted with 100mL ethyl acetate. The extract was washed with 100mL of a saturated aqueous solution of sodium hydrogencarbonate and 100mL of saturated brine and concentrated to give 2.36g of a crude product. The product was purified by column chromatography on pure silica gel to give 2.25g (yield 92.0%) of 5- (1-hydroxyethyl) furo [2, 3-c ] pyridine.

As shown in examples 2 to 5, the present invention provides a method for preparing a pyridinol derivative useful as an intermediate for antiviral agents and the like under mild conditions in a high yield in a manner suitable for industrial production. It also provides synthetic intermediates suitable for use in the above process and processes for their preparation.

Example 6

5-Ethoxycarbonylfuro [2, 3-c ] pyridine (956mg, 5.0mmol) obtained in example 2 was dissolved in 10mL of toluene, 2.55g (7.5mmol) of a 20% ethanol solution of sodium ethoxide was added dropwise to the solution at room temperature, and 661mg (7.5mmol) of ethyl acetate was added dropwise to the solution at room temperature with stirring. After the addition of all of the ethyl acetate was completed, the reaction mixture was heated to 80 ℃ and the reaction was allowed to proceed for 8 hours. The reaction solution was then cooled to 5 ℃ and neutralized with 450mg (7.5mmol) of acetic acid while maintaining the temperature of 5-10 ℃, and the solution was stirred at that temperature for 30 minutes, 1mL of water was added, and the solution was allowed to warm to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5mL of dichloromethane, and the combined organic layers were dried over anhydrous magnesium sulfate and then concentrated on a rotary evaporator to give 851mg of a solid. The solid was recrystallized from a toluene-hexane mixed solvent to give 769mg (yield 66%) of ethyl β -oxo-5-furo [2, 3-c ] pyridylpropionate of 99% purity by HPLC.

¹H-NMR Spectroscopy (270MHz, CDCl)₃，TMS，ppm)δ：1.25(3H，t，J＝7.17Hz)，4.21(2H，q，J＝7.17Hz)，4.25(2H，s)，6.95(1H，d，J＝2.46Hz)，7.85(1H，d，J＝1.97Hz)，8.42(1H，s)，8.88(1H，s).

Example 7

5-Ethoxycarbonylfuro [2, 3-c ] pyridine (956mg, 5.0mmol) was dissolved in 10mL of toluene, 510mg (7.5mmol) of sodium ethoxide was added to the solution at room temperature, and 661mg (7.5mmol) of ethyl acetate was added dropwise with stirring at room temperature. After the addition of ethyl acetate was complete, the reaction mixture was heated to 80 ℃ and the reaction was allowed to proceed for 4 hours. The reaction solution was then cooled to 5 ℃ and neutralized with 450mg (7.5mmol) of acetic acid while maintaining the temperature of 5-10 ℃ and the solution was stirred at that temperature for 30 minutes, then 1ml of water was added and the solution was allowed to warm to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5mL of dichloromethane, the combined organic layers were dried over anhydrous magnesium sulfate and concentrated by a rotary evaporator, and the resulting solid was recrystallized from a toluene-hexane mixed solvent to give 840mg (yield 72%) of ethyl β -oxo-5-furo [2, 3-c ] pyridinepropionate having a purity of 99% by HPLC.

Example 8

1.16g (10.0mmol) of tert-butyl acetate are added dropwise, with stirring, to a solution of 510mg (7.5mmol) of sodium ethoxide in 5mL of toluene at room temperature. Then, a solution of 956mg (5.0mmol) of 5-ethoxycarbonylfuro [2, 3-c ] pyridine in 5mL of toluene was added dropwise to the above solution at room temperature. After all the solution was added, the reaction mixture was heated to 60 ℃ and the reaction was allowed to proceed for 3 hours. The reaction solution was cooled to 5 ℃ and neutralized with 450mg (7.5mmol) of acetic acid while maintaining the temperature of 5-10 ℃ and the solution was stirred at that temperature for 30 minutes, then 1mL of water was added and the solution was allowed to warm to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5mL of dichloromethane, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated by rotary evaporator. The obtained solid was recrystallized from a toluene-hexane mixed solvent to obtain 933mg (yield 80%) of ethyl β -oxo-5-furo [2, 3-c ] pyridylpropionate of 99% purity by HPLC.

Example 9

1.16g (10.0mmol) of tert-butyl acetate are added dropwise, with stirring, to a solution of 405mg (7.5mmol) of sodium methoxide in 5mL of toluene at room temperature. Then, a solution of 956mg (5.0mmol) of 5-ethoxycarbonylfuro [2, 3-c ] pyridine dissolved in 5mL of toluene was added dropwise to the above solution at room temperature. After all the solution was added, the reaction mixture was heated to 60 ℃ and the reaction was allowed to proceed for 3 hours. The reaction solution was cooled to 5 ℃ and neutralized with 450mg (7.5mmol) of acetic acid while maintaining the temperature of 5-10 ℃ and the solution was stirred at that temperature for 30 minutes, then 1mL of water was added and the solution was allowed to warm to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5mL of dichloromethane, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator to yield 971mg of a solid. NMR analysis showed a mixture of methyl β -oxo-5-furo [2, 3-c ] pyridinepropionate, ethyl β -oxo-5-furo [2, 3-c ] pyridinepropionate, and tert-butyl β -oxo-5-furo [2, 3-c ] pyridinepropionate (molar ratio 55: 44: 1). The NMR spectrum of ethyl β -oxo-5-furo [2, 3-c ] pyridylpropionate described above was identical with that of ethyl β -oxo-5-furo [2, 3-c ] pyridylpropionate obtained in example 6.

Beta-oxo-5-furo [2, 3-c ] pyridinepropionic acid methyl ester

¹H-NMR Spectroscopy (270MHz, CDCl)₃，TMS，ppm)δ：3.75(3H，s)，4.29(2H，s)，6.95(1H，d，J＝1.97Hz)，7.85(1H，d，J＝1.98Hz)，8.39(1H，s)，8.88(1H，s).

Beta-oxo-5-furo [2, 3-c ] pyridinepropionic acid tert-butyl ester

¹H-NMR Spectroscopy (270MHz, CDCl)₃，TMS，ppm)δ：1.42(9H，s)，4.13(2H，s)，6.94(1H，d，J＝1.98Hz)，7.83(1H，d，J＝1.98Hz)，8.40(1H，s)，8.88(1H，s).

Example 10

A mixture of 971mg of methyl β -oxo-5-furo [2, 3-c ] pyridinepropionate, ethyl β -oxo-5-furo [2, 3-c ] pyridinepropionate, and tert-butyl β -oxo-5-furo [2, 3-c ] pyridinepropionate obtained in example 9 (molar ratio 55: 44: 1) was dissolved in 20mL of toluene, and 1.04g of 35% hydrochloric acid was added thereto with stirring at room temperature. After the addition was complete, the reaction mixture was heated to 60 ℃ and allowed to react for 3 hours with stirring. The reaction solution was then cooled to room temperature and neutralized with 8.40g of 5% aqueous sodium hydroxide solution. The organic layer was separated, the aqueous layer was extracted twice with 5mL of dichloromethane, and the combined organic layers were dried over anhydrous magnesium sulfate and then concentrated with a rotary evaporator. The resulting solid was recrystallized from a toluene-hexane mixed solvent to give 629mg of 5-acetylfuro [2, 3-c ] pyridine of 99% purity by HPLC (78% yield from 5-ethoxycarbonylfuro [2, 3-c ] pyridine).

Example 11

Ethyl β -oxo-5-furo [2, 3-c ] pyridylpropionate (1.17g, 5.0mmol) was dissolved in 20mL of toluene, and 1.5mL (7.5mmol) of 10N sulfuric acid was added with stirring at room temperature. After the addition was complete, the reaction mixture was heated to 80 ℃ and the reaction was allowed to proceed for 6 hours with stirring. The solution was then cooled to room temperature and neutralized with 12mL of 5% aqueous sodium hydroxide solution. The organic layer was separated, the aqueous layer was extracted twice with 5mL of dichloromethane, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator. The obtained solid was recrystallized from a toluene-hexane mixed solvent to obtain 580mg of 5-acetylfuro [2, 3-c ] pyridine, which was 99% pure by HPLC (yield 72%).

Example 12

Ethyl β -oxo-5-furo [2, 3-c ] pyridylpropionate (583mg, 2.5mmol) obtained in example 7 was dissolved in 10mL of toluene, and 3g of a 10% aqueous sodium hydroxide solution was added thereto with stirring. After the addition was complete, the reaction mixture was heated to 60 ℃ and allowed to react for 8 hours with stirring. Then, it was cooled to room temperature, the organic layer was separated, the aqueous layer was extracted twice with 5mL of dichloromethane, and the combined organic layers were dried over anhydrous magnesium sulfate and then concentrated with a rotary evaporator. The resulting solid was recrystallized from a toluene-hexane mixed solvent to give 205mg (51% yield) of 5-acetylfuro [2, 3-c ] pyridine, which was 99% pure by HPLC.

Example 13

1.16g (10.0mmol) of tert-butyl acetate are added dropwise, with stirring, to a solution of 405mg (7.5mmol) of sodium formate in 5mL of toluene at room temperature. Then, 956mg (5.0mmol) of 5-ethoxycarbonylfuro [2, 3-c ] pyridine dissolved in 5mL of toluene was added dropwise to the above solution at room temperature. After all the solution was added, the reaction mixture was heated to 60 ℃ and the reaction was allowed to proceed for 3 hours. The resulting reaction mixture was further neutralized with 450mg (7.5mmol) of acetic acid, the solution was stirred for 30 minutes, then 1.5mL (7.5mmol) of 5N hydrochloric acid was added, and the solution was stirred at 60 ℃ for 5 hours to effect a reaction. The reaction solution was then allowed to return to room temperature, the organic layer was separated, the aqueous layer was extracted twice with 5mL of dichloromethane, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated with a rotary evaporator. The resulting solid was recrystallized from a toluene-hexane mixed solvent to give 580mg (yield 72%) of 5-acetylfuro [2, 3-c ] pyridine, which was 99% pure by HPLC.

Example 14

5-Acetylfuro [2, 3-c ] pyridine (2.42g, 15.0mmol) obtained in example 13 was dissolved in toluene (30mL), and the solution was cooled to 0 ℃. To the cooled solution, 16.0mL (16.0mmol) of a 1.0M toluene solution of diisobutylaluminum hydride was added, the solution was stirred at the above temperature for 2 hours, and the reaction mixture was poured into 100mL of 5% aqueous ammonium chloride solution which had been cooled on ice and extracted twice with 100mL of ethyl acetate. The extract was washed with 100mL of a saturated aqueous solution of sodium hydrogencarbonate and 100mL of saturated brine, and the solvent was concentrated to obtain 2.36g of a crude product. The product was purified by silica gel column chromatography to give 2.25g (yield 92.0%) of 5- (1-hydroxyethyl) furo [2, 3-c ] pyridine.

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

As shown in examples 6 to 14, the present invention can provide a method for producing a pyridine derivative useful as an intermediate for antiviral agents and the like under mild conditions in a high yield in a manner suitable for industrial production. Synthetic intermediates useful in the above process and methods for their preparation are also provided.

The specifications of Japanese patent application No.9-291075, filed 1997 on month 10 and 23, No.10-64862, filed 3 and 16 on 1998, and No.10-219943, filed 8 and 4 on 1988, the full disclosures of the claims and summaries of which are hereby incorporated by reference.

Claims (3)

1. A pyridine carbonyl derivative represented by the general formula II-1:

in the formula (I), the compound is shown in the specification,

R⁵is represented by-CHR¹R²Wherein R is¹And R²Each independently represents a hydrogen atom or a C1-8 alkyl group;

q represents a divalent group selected from the group consisting of-O-and-S-.

2. A process for preparing a pyridine carbonyl derivative represented by the general formula II-1,

in the general formula II-1, the compound,

R⁵is represented by-CHR¹R²Wherein R is¹And R²Each independently represents a hydrogen atom or a C1-8 alkyl group; q

Represents a divalent group selected from-O-and-S-;

the method comprises the following steps:

pyridine ester derivatives represented by the general formula I-1

In the general formula I-1, Z¹represents-COX, wherein X represents C1-8 alkoxy; and Q is as defined above, and,

and formula R⁵Alkylating agent reaction of Li, wherein R⁵The definition is the same as above.

3. A process for preparing a pyridine carbonyl derivative represented by the general formula II-1,

in the general formula II-1, the compound,

R⁵is represented by-CHR¹R²Wherein R is¹And R²Each independently represents a hydrogen atom or a C1-8 alkyl group; q

Represents a divalent group selected from-O-and-S-;

the method comprises the following steps:

hydrolyzing and decarboxylating a pyridine beta-keto ester derivative represented by the general formula V-1:

in the general formula V-1, R¹、R²And Q is as defined above; and R⁴Represents a C1-8 alkyl group; to obtain a pyridine carbonyl derivative represented by the general formula II-1.