WO2005058860A1

WO2005058860A1 - Process for producing 4-(un)substituted tetrahyropyran-4-carboxylic acid compound or ester compound thereof

Info

Publication number: WO2005058860A1
Application number: PCT/JP2004/018942
Authority: WO
Inventors: Shigeyoshi Nishino; Kenji Hirotsu; Hidetaka Shima; Keiji Iwamoto; Takashi Harada
Original assignee: Ube Industries, Ltd.
Priority date: 2003-12-19
Filing date: 2004-12-17
Publication date: 2005-06-30
Also published as: JP2011178787A; JP4867350B2; JP5673729B2; JP2013189445A; JP5304818B2; JPWO2005058860A1

Abstract

A process for producing a 4-(un)substituted tetrahydropyran-4-carboxylic acid compound or an ester compound thereof which are represented by the formula (1): (1) (wherein R1 represents hydrogen or a hydrocarbon group; R2 represents hydrogen or an optionally substituted hydrocarbon group; and R3 represents hydrogen or a hydrocarbon group), characterized by reacting a 4-(un)substituted 4-cyanotetrahydropyran compound represented by the formula (2): (2) (wherein R1 and R2 are the same as defined above) with water or an alcohol which are represented by the formula (3): R3OH (3) (wherein R3 is the same as defined above) in the presence of an acid or base.

Description

Specification

(4) Preparation of mono- or unsubstituted tetrahydropyran- (IV) monocarboxylic acid or its ester compound

Technical field

The present invention relates to a method for producing a 4-substituted or unsubstituted tetrahydropyran_4_carboxylic acid compound or an ester aldehyde compound thereof from a 4_substituted or unsubstituted 4-cyanotetrahydropyran compound, and a raw material compound thereof. The present invention relates to a method for producing a certain 4-substituted or unsubstituted-4-cyanotetrahydropyran compound. The 4-substituted or unsubstituted tetrahydropyran-4-carboxylic oxide compound or an ester compound thereof is a compound useful as a raw material for a pharmaceutical or an agricultural chemical or a synthetic intermediate.

Background art

[0002] Conventionally, as a method for producing a 4_-substituted tetrahydropyran-4-carboxylic acid compound, for example, tetrahydropyran_4_carboxylic acid is used in the presence of lithium diisopropylamide synthesized from diisopropylamine and n_butyllithium. And methyl iodide are reacted in a mixed solvent of hexane and tetrahydrofuran for 3.5 days to produce 4-methyltetrahydropyran_4_carboxylic acid (for example, see Patent Document 1). However, in this method, the reaction time is extremely long, and the reaction system is complicated due to the use of lithium diisopropylamide which is a strong base, which is disadvantageous as an industrial method for producing a 4-substituted tetrahydropyran-4-carboxylic acid compound. Met.

[0003] Also, as a method for producing 4-unsubstituted tetrahydropyran-4-carboxylic acid, for example, tetrahydropyran-4,4-dicarboxylic acid is heated to 185 ° C to obtain an isolation yield of 64%. A method for obtaining tetrahydropyran-4-carboxylic acid is known (for example, see Patent Document 2). However, the above method is not satisfactory as an industrial method for producing a 4-unsubstituted tetrahydropyran-4-carboxylic acid compound which requires a high reaction temperature and has a low yield.

[0004] Further, as a method for producing 4-unsubstituted tetrahydropyran-4-carboxylic acid ester, a method of decarboxylating tetrahydropyran-4,4-dicarboxylic acid ester is known (eg, For example, see Patent Document 3). However, this method requires a large amount of tetra-n-butylphosphonium bromide, and has problems such as a high reaction temperature and a low yield of the target compound. This is disadvantageous as an industrial method for producing pyran-4-carboxylic acid ester.

[0005] On the other hand, as a method for producing a 4-substituted-4-cyanotetrahydropyran compound from a 4-cyanotetrahydropyran compound, for example, lithium diisopropylamide synthesized from diisopropylamine and n_butyllithium is used. In the presence of 2,3,5,6-tetrahydro-4H-pyran_4_carbonitrile (4-cyanotetrahydropyran), 1,3-dimethylimidazolidin-2-one and 1- (bromomethyl) _4_ [2 -(Trimethylsilyloxyl) ethyl] benzene is reacted in a mixed solvent of hexane and tetrahydrofuran to give 4 _ [[4- (2-hydroxyethyl) phenyl] methyl] tetrahydropyran-4-carbondiene. A method for producing toril is disclosed (for example, see Patent Document 4). However, this method requires that 1,3-dimethylimidazolidin-2-one be used in excess with respect to the substrate, and the reaction system is complicated and 4-substituted-4-cyanotetrahydropyran It was disadvantageous as an industrial production method of the compound.

[0006] Further, as a method for producing a 4-unsubstituted-4-cyanotetrahydropyran compound which is also used as a raw material compound in the present invention, for example, bis (2-chloroethyl) ether and ethyl cyanoacetate are used. After reacting to give 4-cyanotetrahydropyran-4-ethyl carboxylate, this is hydrolyzed to obtain 4-cyanotetrahydropyran-4-carboxylic acid, which is then heated to 180-200 ° C. To produce 4-cyanotetrahydropyran with an overall acquisition yield of 2.3% (for example, see Non-Patent Document 1). However, this method is not satisfactory as an industrial process for producing 4-unsubstituted-4-cyanotetrahydropyranich compounds having many reaction steps and extremely low yields.

[0007] Patent Document 1: Japanese Patent Publication No. 2002-501066

Patent Document 2: International Publication WO03 106418

Patent Document 3: JP-A-2000-281672

Patent Document 4: JP-A-5-279319

Non-patent literature l: J. Chem. So, 1930, 2525

Disclosure of the invention Problems the invention is trying to solve

[0008] The first object of the present invention is to provide a 4-substituted or unsubstituted-4-cyanotetrahydropyran compound under mild conditions that solves the above problems and requires no complicated operations. 4-substituted or unsubstituted tetrahydropyran-4-carboxylic acid compound capable of producing a 4-substituted or unsubstituted tetrahydropyran-4-carboxylic acid compound or an ester compound thereof in a high yield from Another object of the present invention is to provide a method for producing the ester compound. A second object of the present invention is to solve the above problems, and to obtain 4-substituted or unsubstituted-4-cyanotetrahydridopyran compounds from 4-cyanotetrahydropyran compounds in high yield without requiring complicated operations. To provide an industrially suitable method for producing a 4-substituted or unsubstituted 4-cyanotetrahydropyrani conjugate.

A third object of the present invention is to solve the above problems, and to produce a 4-cyanotetrahydropyran compound from a 4-substituted tetrahydropyran compound in a high yield by a simple method. An object of the present invention is to provide a method for producing a 4-cyanotetrahydropyrani conjugate.

Means for solving the problem

[0009] The first invention of the present invention provides a compound of the formula (2) in the presence of an acid or a base:

[0011] In the formula, R ¹ represents a hydrogen atom or a hydrocarbon group; R ² represents a hydrogen atom or a substituent having a hydrogen atom or a substituent;

And a 4_-substituted or unsubstituted-4-cyanotetrahydropyran compound represented by the formula (3):

R ³ OH (3) wherein R ³ represents a hydrogen atom or a hydrocarbon group,

Wherein water or alcohol represented by the following formula is reacted:

[0012]

R .C0 ₂ R ³ [0013] where:

R ² and R ³ are as defined above,

And a method for producing a 4-substituted or unsubstituted tetrahydropyran-4-carboxylic acid compound or an ester compound thereof.

[0014] The second invention of the present invention provides a compound of the formula (4):

Wherein R ¹ is as defined above,

And a 4_-unsubstituted_4-cyanotetrahydropyrani conjugate represented by the formula:

R ² X (5)

In the formula, R ² has the same meaning as described above, and X represents a leaving group.

A method for producing a 4-substituted or unsubstituted 4-cyanotetrahydropyrani conjugate represented by the above formula (2), characterized by reacting a reaction reagent represented by the following formula:

[0016] The third invention of the present invention provides (6):

In the formula, X and R ¹ are as defined above,

A method for producing a 4-cyanotetrahydropyrani conjugate represented by the formula (4), characterized by reacting a 4-substituted tetrahydropyran compound represented by the formula with a cyanating agent.

The invention's effect

[0018] According to the present invention, 4-substituted or unsubstituted tetrahydropyran can be produced in a high yield from a 4-substituted or unsubstituted-4-cyanotetrahydropyran compound under mild conditions without requiring complicated operations. An industrially suitable method for producing a 4-substituted or unsubstituted tetrahydropyran-4-carboxylic acid compound or an ester compound thereof capable of producing a 4-carboxylic acid compound or an esterified compound thereof. I can do it.

According to the present invention, 4-unsubstituted-4-cyanotetrahydrovilla without complicated operation An industrially suitable method for producing a 4-substituted-4-cyanotetrahydropyran compound, which is capable of producing a 4-substituted-4-cyanotetrahydropyran compound from a pyridine compound in high yield, can be provided. I can do it.

According to the present invention, a 4-cyanotetrahydropyrani conjugate can be produced in a high yield from a 4-substituted tetrahydropyrani conjugate by a simple method. Providing a recipe can be provided.

BEST MODE FOR CARRYING OUT THE INVENTION

[0019] The 4-substituted or unsubstituted-4-cyanotetrahydrosilane compound used in the first invention of the present invention is represented by the above formula (2). In the formula (2), R ¹ is a hydrogen atom or a hydrocarbon group, and examples of the hydrocarbon group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. A straight-chain or branched alkyl group having 1 to 6 carbon atoms; an aralkyl group having 7 to 12 carbon atoms such as a benzyl group, a phenethyl group and a phenylpropyl group; a phenyl group, a tolyl group, a xylyl group, and an ethylphenyl group And an aryl group in which a linear or branched alkyl group having 1 to 6 carbon atoms is substituted with 0 to 6 phenyl groups, naphthyl groups, anthryl groups and the like. These groups include various isomers.

Further, R ² is a hydrogen atom or a hydrocarbon group which may have a substituent, and the hydrocarbon group has the same meaning as that of R ¹ . These groups include various isomers. The aforementioned hydrocarbon group for R ² may have a substituent. Examples of the substituent include a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, a substituent formed through a sulfur atom, and a halogen atom.

Examples of the substituent formed through the carbon atom include an alkyl group such as a methyl group, an ethyl group, a propynole group, a butyl group, a pentyl group, and a hexyl group; a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group. Groups, cycloalkyl groups such as cyclohexyl group and cyclobutyl group; alkenyl groups such as butyl group, arylinyl group, propenyl group, cyclopropenyl group, cyclobutyl group, cyclopentyl group; quinolyl group, pyridyl group, and pyrrolidyl group Heterocyclic groups such as phenyl, pyrrolyl, furyl and phenyl groups; aryl groups such as phenyl, tolyl, fluorophenyl, xylyl, biphenyl, naphthyl, anthryl and phenanthryl; acetyl, Propionyl group, atariloyl group, bivaloyl group, cyclohexylcal Acyl groups such as bonyl, benzoyl, naphthoyl and toluoyl groups (which may be acetalized); carboxyl groups; alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl groups; and phenyl groups such as phenoxycarbonyl groups. A lyloxycarbonyl group; and a cyano group. These groups include various isomers.

Examples of the substituent formed via the oxygen atom include a hydroxyl group; a methoxyl group, an ethoxyl group, a propoxyl group, a butoxyl group, a pentyloxyl group, a hexyloxyl group, a heptyloxyl group, a benzyloxyl group and the like. Alkoxyl group; phenyloxyl group, tolyloxyl group, aryloxyl group such as naphthyloxyl group. These groups include various isomers.

Examples of the substituent formed via the nitrogen atom include primary amino groups such as methylamino, ethylamino, butylamino, cyclohexylamino, phenylamino, and naphthylamino; dimethylamino, getylamino, Secondary amino groups such as dibutylamino group, methylethylamino group, methylbutylamino group, diphenylamino group, N-methyl-N-methanesulfonylamino group; morpholino group, piperidino group, piperazinyl group, virazolidinyl group, pyrrolidino group And heterocyclic amino groups such as indolyl groups; and imino groups. In addition, these groups include various isomers.

Examples of the substituent formed via the sulfur atom include a mercapto group; a thioalkoxyl group such as a thiomethoxyl group, a thioethoxyl group, and a thiopropoxyl group; a thiophenoxynole group, a thiotoluyloxyl group, and a thionaphthyl And a thioaryloxy group such as a xyl group. These groups include various isomers.

[0025] Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0026] Examples of the acid used in the reaction of the first invention include sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, formic acid, acetic acid, chloroacetic acid, Forces such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Preferably, sulfuric acid, hydrochloric acid, and phosphoric acid are used. These acids may be used alone or in combination of two or more.

[0027] As the base used in the reaction of the first invention, for example, lithium hydroxide, hydroxyl Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate and potassium hydrogen carbonate Alkali metal bicarbonates; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; amines such as triethylamine and tributylamine; and pyridines such as pyridine and picoline S, preferably sodium hydroxide, hydroxide Potassium is used. These bases may be used alone or in combination of two or more.

[0028] The amount of the acid and the base to be used is preferably 0.150 mol, more preferably 1.0-20 mol, per 1 mol of the 4-substituted or unsubstituted-4-cyanotetrahydropyrani conjugate. .

[0029] The reaction of the first invention is desirably performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include water; alcohols such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol; and N-dimethylforma. Amides such as amides, N, N-dimethylacetoamide, N-methylpyrrolidone; Ureas such as Ν, Ν'-dimethylimidazolidinone; Sulfoxides such as dimethyl sulfoxide; Getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc. Ethers; aliphatic hydrocarbons such as hexane, heptane, and cyclohexane; halogenated hydrocarbons such as methylene chloride and dichloromethane; and aromatic hydrocarbons such as benzene, toluene, and xylene. Preferably, water and alcohols are used. These solvents may be used alone or in combination of two or more.

[0030] The amount of the solvent to be used is appropriately adjusted depending on the uniformity of the reaction and the stirring property. Preferably it is 0.1 20 ml.

[0031] The water or alcohol used in the reaction of the first invention is represented by the above formula (3). In the formula (3), R ³ is a hydrogen atom or a hydrocarbon group. Specific examples of the hydrocarbon group include a carbon atom such as a methyl group, an ethyl group, a propyl group, and a butyl group. A linear or branched alkyl group having 1 to 6 children; an aralkyl group such as a benzyl group or a phenyl group; a force S such as an aryl group such as a phenyl group or a tolyl group, preferably an alkyl group, and more preferably a methyl group. , An ethyl group. These groups include various isomers. [0032] The amount of the water or alcohol used is preferably 1 to 100 mol, more preferably 2 to 20 mol, per 1 mol of the 4-substituted or unsubstituted-4-cyanotetrahydropyran compound.

[0033] The amount of the acid to be used is preferably 0.1 to 10 mol, more preferably 0.5 5.0 mol, per 1 mol of the 4-substituted or unsubstituted-4-cyanotetrahydropyran compound.

[0034] The reaction of the first invention is, for example, a reaction in which a 4_-substituted or unsubstituted-4-cyanotetrahydropyran compound, an acid or a base, water or an alcohol, and a solvent are mixed and stirred. It is performed by the method described above. At this time, the reaction temperature is preferably 0 200 ° C, more preferably 10 130 ° C, and the reaction pressure is not particularly limited.

[0035] The power of obtaining a 4_-substituted or unsubstituted tetrahydropyran-4_carboxylic oxide compound or an ester compound thereof by the reaction of the first invention. This is after neutralization, extraction, filtration, concentration, distillation, It is isolated and purified by general methods such as recrystallization, crystallization, and column chromatography.

[0036] The 4-substituted-4-cyanotetrahydropyran compound represented by the formula (2) used in the first invention can be prepared by reacting the compound of the formula (4):

Wherein R ¹ is as defined above,

And a 4-unsubstituted-4-cyanotetrahydropyranich compound represented by the formula (5):

^[0039] R ^ X (5)

By reacting the reaction reagent represented by the formula (1), the second invention of the present invention facilitates production.

The 4-unsubstituted-4-cyanotetrahydropyran compound used in the above reaction of the second invention is represented by the above formula (4). In the formula (4), R ¹ has the same meaning as described above.

[0042] The reaction reagent used in the reaction of the second invention is represented by the above formula (5). That X in the formula (5) is a leaving group, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methanesulfonyloxy group, an ethanesulfonyloxy group and a trifluoromethane Alkylsulfonyloxy group such as sulfonyloxy group; alkoxysulfonyloxy group such as methoxysnorreonyoxy group; benzenesulfonyloxy group, p-toluenesulfonyloxy group, p-fluorobenzenesulfonyloxy group, p_ And arylsulfonyloxy groups such as bromobenzenesulfonyloxy group and p-methoxybenzenesulfonyloxy group.

[0044] The amount of the reaction reagent to be used is preferably 1.0 to 10 mol, more preferably 1.05 mol, per 1 mol of the 4-unsubstituted-4-cyanotetrahydropyran compound.

[0045] The base used in the reaction of the second invention includes, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydrogencarbonate; Alkali metal bicarbonates such as potassium bicarbonate; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkaline earth metal hydrides such as calcium hydride Alkali metal alkyls such as methyllithium, n-butyllithium, sec-butyllithium, and t-butyllithium; alkali metal amines such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium amide, and sodium bis (trimethylsilyl) amide used. In addition, you may use these bases individually or in mixture of 2 or more types.

[0046] The amount of the base to be used is preferably 1.0 to 10 mol, more preferably 1.0 to 5 mol, per 1 mol of the 4-unsubstituted-4-cyanotetrahydropyran compound.

[0047] The reaction of the second invention is desirably performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohols such as methanol, ethanol, isopropyl alcohol, and t_butyl alcohol; ketones such as acetone, methylethyl ketone, and methyl isobutyl ketone; Amides such as Ν, Ν-dimethylformamide, Ν, Ν_dimethylenolacetoamide, and Ν-methylpyrrolidone; urines such as Ν, Ν, -dimethylimidazolidinone; sulfoxides such as dimethyl sulfoxide; getyl ether; Ethers such as isopropynole ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene, but preferably amides, ethers and aromatics Hydrocarbons are used. These solvents may be used alone or in combination of two or more.

[0048] The amount of the solvent to be used is appropriately adjusted depending on the uniformity of the reaction and the stirring property, but it is preferably 1 to 50 ml, and more preferably 2 to 4 unsubstituted-4-cyanotetrahydropyran compound lg. One is 10ml.

[0049] In the reaction of the second invention, for example, after mixing and stirring a 4_unsubstituted-4-cyanotetrahydropyran compound, a base and a solvent, the reaction reagent is added, and the mixture is stirred. It is performed by a method such as reaction. The reaction temperature at that time is preferably -20 180 ° C, more preferably -5 120 ° C, and the reaction pressure is not particularly limited.

[0050] The reaction of the second invention yields a 4-substituted-4-cyanotetrahydropyran compound, which is neutralized, extracted, filtered, concentrated, distilled, recrystallized, crystallized after completion of the reaction. It is isolated and purified by a common method such as column chromatography.

[0051] In the present invention, 4-unsubstituted-4- represented by the formula (4) used in the second invention is used.

Can be easily produced according to the third invention of the present invention by reacting a 4-substituted tetrahydropyran compound represented by the following formula with a cyanating agent.

[0054] The 4-substituted tetrahydropyrani conjugate used in the reaction of the third invention is represented by the above formula (

Indicated by 6). In the formula (6), X is a leaving group, specifically, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom; a methanesulfonyloxy group, an ethanesulfonyloxy group, Alkyl sulfonyl / reoxy groups such as trifluoromethanesulfonyloxy group; benzenesulfonyloxy group, p-toluenesulfonyloxy group, p-bromobenzenesulfonyloxy group, p-methoxybenzenesulfonyloxy group, etc. And a reelsulfonyloxy group. R ¹ has the same meaning as described above.

[0055] Examples of the cyanating agent used in the reaction of the third invention include lithium cyanide. , Sodium cyanide, potassium cyanide, copper cyanide, iron cyanide, tetraethylammonium cyanide and the like. These cyanating agents may be used alone or in combination of two or more.

[0056] The amount of the cyanating agent to be used is preferably 1.010 mol, more preferably 1.1 to 5.0 mol, per 1 mol of the 4-substituted tetrahydropyran compound.

[0057] The reaction of the third invention is desirably performed in a solvent. The solvent used is one that does not inhibit the reaction, and is not particularly limited as long as it is, for example, water; methanol, ethanol, isopropylinorenocone, t-butinoleanorecone, ethylene glycolone, Alcohols such as triethylene glycolonole; amides such as Ν, Ν-dimethylformamide, Ν, ァ _dimethylacetoamide, Ν-methinolepyrrolidone; ureas such as Ν, Ν'-dimethylimidazolidinone; dimethyl sulfoxide Sulfoxides, etc .; ethers, such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane; aromatic hydrocarbons, such as benzene, toluene, xylene; nitriles, such as acetonitrile, propionitrile, etc. Preferably, alcohols Amides and sulfoxides are used. These solvents may be used alone or in combination of two or more.

[0058] The amount of the solvent to be used is appropriately adjusted depending on the uniformity and stirring property of the reaction solution. One 20g

[0059] The reaction of the third invention is carried out, for example, by a method of mixing a 4-substituted tetrahydropyranich compound, a cyanating agent and a solvent, and reacting the mixture with stirring. The reaction temperature at that time is preferably 20 to 200 ° C, more preferably 40 to 120 ° C, and the reaction pressure is not particularly limited. Since toxic hydrogen cyanide may be generated during the reaction of the present invention, it is desirable that a base (for example, an organic amine or an alkali metal salt) is present in the system in advance.

[0060] In order to adjust the reactivity, a quaternary ammonium salt such as tetramethylammonium chloride and tetraethylammonium bromide; and an alkali metal halide such as sodium iodide and potassium iodide may be added. .

[0061] The 4-unsubstituted-4-cyanotetrahydropyrani conjugate obtained by the reaction of the third invention is For example, it is isolated and purified by general methods such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, and column chromatography.

Example

Next, the present invention will be described specifically with reference to examples, but the scope of the present invention is not limited thereto.

Example 1 (Synthesis of 4-cyanotetrahydropyran)

In a 20-ml glass flask equipped with a stirrer, thermometer, and reflux condenser, 1.85 g (10.2 mmol) of tetrahydroviranyl-4-methanesulfonate, potassium cyanide

1.0 g (15.4 mmol) and 10 ml of dimethyl sulfoxide were added, and the mixture was reacted at 80 ° C. for 7 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method), and it was found that 0.50 g of 4-cyanotetrahydropyran was produced (reaction yield: 44%).

Example 2 (Synthesis of 4-cyanotetrahydropyran)

1.0 g (15.4 mmol), 2.07 g (20.4 mmol) of triethylamine and 10 ml of dimethyl sulfoxide were added, and reacted at 80 ° C. for 7 hours with stirring. After the completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 0.47 g of 4-cyanotetrahydropyran was produced (reaction yield: 41%).

Example 3 (Synthesis of 4-cyanotetrahydropyran)

In a 20 ml glass flask equipped with a stirrer, thermometer and reflux condenser, 2.62 g (10.2 mmol) of tetrahydroviranyl-4-p-toluenesulfonate, potassium cyanide

1.0 g (15.4 mmol) and 10 ml of dimethyl sulfoxide were added, and the mixture was reacted at 80 ° C. for 7 hours with stirring. After the completion of the reaction, the reaction mixture was analyzed by gas chromatography (internal standard method). As a result, 0.46 g of 4-cyanotetrahydropyran was produced (reaction yield: 41%).

Example 4 (Synthesis of 4-cyanotetrahydropyran)

In a 20 ml glass flask equipped with a stirrer, thermometer and reflux condenser, 1.69 g (10.2 mmol) of 4-bromotetrahydropyran, 1.0 g (15.4 mmol) of potassium cyanide, and 10 ml of dimethylolresulfoxide were added. The reaction was carried out at 80 ° C for 7 hours with stirring. After the reaction, Analysis of the reaction solution by gas chromatography (internal standard method) revealed that 0.10 g of 4-cyanotetrahydropyran was produced (reaction yield: 9%).

Reference Example (Synthesis of 4-cyanotetrahydropyran)

Under a nitrogen atmosphere, 4.6 g (31.9 mmol) of copper (I) oxide and 200 g of pyridine were added to a glass flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser under a nitrogen atmosphere and stirred. The temperature was raised to 100 ° C. Then, a solution of 200 g (1.28 mol) of 4-cyanotetrahydropyran-4-carboxylic acid having a purity of 99% dissolved in 400 g of pyridine is slowly added dropwise while maintaining the temperature of the reaction solution at 100 to 110 ° C. And reacted at 100-110 ° C for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, and while stirring, 500 ml of water, 650 ml (7.80 mol) of concentrated hydrochloric acid and 500 ml of toluene were sequentially added. The aqueous layer and the organic layer (toluene layer) were separated, and the aqueous layer was extracted three times with 500 ml of toluene. The organic layer and the toluene extract were combined and concentrated under reduced pressure. The obtained concentrate was distilled under reduced pressure (100 to 120 ° C, 2.0 to 2.7 kPa) to obtain 133.5 g of 4-cyanotetrahydropyran having a purity of 99% (area percentage by gas chromatography) as a colorless liquid. (Isolation yield: 93%).

[0068] The physical properties of 4-cyanotetrahydropyran were as follows.

CI_MS (m); 112 (M + 1)

'H-NMRlCDCl, δ (ppm)); 1.63-1.74 (2H, m), 1.80-1.89 (2H, m), 3.04-3.11 (lH, m)

Three

, 3.43—3.50 (2H, m), 3.67—3.75 (2H, m)

Example 6 (Synthesis of 4-methyl-4-cyanotetrahydropyran)

1.0 g (9.0 mmol) of 4-cyanotetrahydropyran and 5 ml of dry tetrahydrofuran were added to a 30-ml glass flask equipped with a stirrer, a thermometer, and a dropping funnel. While maintaining the temperature at 1C, 10.8 ml (10.8 mmol) of a 1.0 mol / l lithium bis (trimethylsilyl) amide solution in tetrahydrofuran was slowly dropped dropwise, and the mixture was stirred at the same temperature for 1.5 hours. Next, 3.8 g (27 mmol) of methane iodide was slowly added dropwise, followed by a reaction at room temperature for 2 hours. After the reaction was completed, 15 ml (15 mmol) of 1.0 mmol / l hydrochloric acid was added to the obtained reaction solution under ice-cooling, and the reaction solution was concentrated. After 10 ml of an aqueous solution of saturated sodium chloride salt was added to the concentrated solution, extraction was performed twice with 30 ml of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 0.98 g of 4_methyl-4-cyanotetrahydropyran as a pale yellow liquid (isolated Yield: 87%).

Physical properties of 4-methyl-4-cyanotetrahydropyran were as follows.

[0070] CI-MS (m / e); 126 (M + l)

'H-NMRCCDCl, δ (ppm)); 1.42 (3H, s), 1.56--1.66 (2H, m), 1.82 1.89 (2H

3, m), 3.65-3.74 (2H, m), 3.92 3.98 (2H, m)

Example 7 (Synthesis of 4-methyltetrahydropyran_4_carboxylic acid)

In a 30 ml glass flask equipped with a stirrer, thermometer, and dropping funnel, add 0.8 g (6.4 mmol) of 4-methylen-4-cyanotetrahydropyran and an aqueous 8 mol / l sodium hydroxide solution.

3.5 ml (2.8 mmol) was prepared and stirred at 100 ° C. for 8 hours. After the reaction was completed, 3.0 ml (36 mmol) of 12 mmol / l hydrochloric acid was added to the obtained reaction solution under ice-cooling, then 40 ml of water and 50 ml of chloroform were added, and the organic layer was separated. The aqueous layer was extracted with 50 ml of getyl ether, and then combined with the organic layer and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 0.72 g of 4-methyltetrahydropyran-4-carboxylic acid as a pale yellow solid (isolation yield: 78%).

Physical properties of 4-methyltetrahydropyran-4-carboxylic acid were as follows.

[0072] CI-MS (m / e); 145 (M + l)

'H-NMRlCDCl, δ (ppm)); 1.30 (3H, s), 1.49-1.58 (2H, m), 2.06--2.12 (2H, m), 3.52

Three

One 3.61 (2H, m), 3.80-3.87 (2H, m), 11.5 (lH, brs)

Example 8 (Synthesis of tetrahydropyran-4-carboxylic acid)

In a 300 ml glass flask equipped with a stirrer, thermometer and reflux condenser, 33.8 g (0.3 mol) of 99% pure 4-cyanotetrahydropyran synthesized in Example 5, 4 mol / l hydroxyl 150 ml (0.6 mol) of sodium hydroxide solution and 34 ml of methanol were added, and the mixture was reacted at 90 ° C. for 10 hours with stirring. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and under ice-cooling, 12 ml / l hydrochloric acid 50 ml (0.6 mol) was added to the obtained concentrated solution, followed by 170 ml of ethyl acetate, and the organic layer was separated. . The aqueous layer was extracted with 102 ml of ethyl acetate, and then dried with anhydrous magnesium sulfate together with the organic layer. After filtration, the filtrate was concentrated under reduced pressure to obtain 34.6 g of tetrahydropyran_4_carboxylic acid as a white solid (isolation yield: 74%).

Physical properties of tetrahydropyran-4-carboxylic acid were as follows.

[0074] Melting point: 83-84. C CI_MS (m); 131 (M + 1)

'H-NMRlCDCl, δ (ppm)); 1.74-1.92 (4H, m), 2.54-2.64 (lH, m), 3.41-3.50 (2H, m)

Three

, 3.96-4.02 (2H, m), 10.80 (lH, brs)

Example 9 (Synthesis of tetrahydropyran_4_carboxylic acid)

In a 50-ml glass flask equipped with a stirrer, thermometer and reflux condenser, 1.07 g (9.5 mmol) of 4-cyanotetrahydropyran with a purity of 99% synthesized in Example 5 and 6 mol / l hydrochloric acid 10 ml (60 mmol) were mixed and reacted at 80 90 ° C. for 7 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 1.06 g of tetrahydropyran-4-hydroxysulfonic acid was produced (reaction yield: 86%).

Example 10 (Synthesis of methyl tetrahydropyran_4_carboxylate)

Under a nitrogen atmosphere, a 99% pure 4-cyanotetrahydropyran synthesized in Example 5 was placed in a 300-ml glass flask equipped with a stirrer, a thermometer, and a reflux condenser.

22.8 g (197.4 mmol), 60 g (600 mmol) of 98% sulfuric acid and 130 ml (3.21 mol) of methanol were added, and the mixture was reacted at 70-75 ° C for 10 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature, 100 ml of water was added, and the organic layer and the aqueous layer were separated. Next, the aqueous layer was extracted three times with 200 ml of ethyl acetate, and then the organic layer and the ethyl acetate extract were mixed and concentrated under reduced pressure. The obtained concentrated solution was distilled under reduced pressure (75-76 ° C, 1.2-1.3 kPa) to obtain 18.3 g of methyl tetrahydropyran-4-carboxylate having a purity of 98.7% (area percentage by gas chromatography) as a colorless liquid. Obtained (isolation yield: 63.5%).

Physical properties of the methyl tetrahydropyran-4-carboxylate were as follows.

[0077] CI_MS (m); 145 (M + 1)

'H-NMRCCDCl, δ (ppm)); 1.71 1.81 (2H, m), 1.82 1.86 (2H, m), 2.50-2.60 (lH, m)

Three

, 3.42 3.47 (2H, m), 3.67 (3H, s), 3.93 3.98 (2H, m)

Industrial applicability

According to the present invention, 4-substituted or unsubstituted 4-cyanotetrahydropyran compounds can be obtained in high yield from 4-substituted or unsubstituted 4-cyanotetrahydropyran compounds under mild conditions without requiring complicated operations. -An industrially suitable 4-substituted or unsubstituted tetrahydropyran-4-carboxylic acid compound or an ester thereof capable of producing a 4-carboxylic acid compound or an esterified compound thereof. The present invention can provide a method for producing a compound.

The 4-substituted or unsubstituted tetrahydropyran-4-carboxylic acid compound or its esterified compound is a compound useful as a raw material for a pharmaceutical or an agricultural chemical or a synthetic intermediate.

The present invention also relates to a method for producing a 4-substituted-4-cyanotetrahydropyrani conjugate from a 4_unsubstituted-4-cyanotetrahydropyrani conjugate. The 4-substituted or unsubstituted 4-cyanotetrahydropyran compound is a compound useful as a raw material of a pharmaceutical or an agricultural chemical or a synthetic intermediate.

The present invention further relates to a process for producing a 4-pyranated 4-substituted-4-cyanotetrahydropyran compound from a 4-substituted tetrahydropyran compound. The 4-unsubstituted-4-cyanotetrahydropyrani conjugate is a compound useful as a raw material for pharmaceuticals and agricultural chemicals and as a synthetic intermediate.

Claims

The scope of the claims

[1] Formula (2) in the presence of an acid or a base

In the formula, R ¹ represents a hydrogen atom or a hydrocarbon group, and R ² represents a hydrocarbon group having a hydrogen atom or a substituent,

And a 4_-substituted or unsubstituted-4-cyanotetrahydropyran compound represented by the formula:

R ³ OH (3) wherein R ³ represents a hydrogen atom or a hydrocarbon group,

Wherein water or alcohol represented by the following formula is reacted:

Where

R ² and R ³ are as defined above,

A method for producing a 4-substituted or unsubstituted tetrahydropyran-4-carboxylic acid compound or an ester compound thereof represented by the formula:

[2] The process according to claim 1, wherein the reaction is carried out in a solvent.

[3] R ¹ is a hydrogen atom or a linear or branched alkyl group having 16 carbon atoms, R ² is a hydrogen atom or a linear or branched alkyl group having 16 carbon atoms, R ^2. The method according to claim 1, wherein ³ is a hydrogen atom or a linear or branched alkyl group having 1 to 16 carbon atoms.

[4] The reaction is carried out at 200 ° C. in the presence of 0.1-50 mol of an acid or base per 1 mol of the 4-substituted or unsubstituted -4-4-cyanotetrahydropyran compound of the formula (2) The production method described in paragraph 1.

[5] A 4-substituted-4-cyanotetrahydropyran compound represented by the formula (2): In the presence of a base, a compound of the formula (4):

Wherein R ¹ is as defined above,

4-unsubstituted -4- represented by the formula (5)

R ² X (5) wherein R ² has the same meaning as described above, and X represents a leaving group;

2. The process according to claim 1, which is obtained by reacting a reaction reagent represented by the following formula.

[6] The production method according to claim 5, wherein the reaction is carried out in a solvent.

[7] The process according to claim 5, wherein the reaction temperature is −20 180 ° C.

[8] A compound represented by the formula (4) is reacted with a compound represented by the formula (6):

In the formula, R ¹ has the same meaning as described above, and X represents a leaving group.

6. The process according to claim 5, which is obtained by reacting a 4-substituted tetrahydropyran compound represented by the formula (1) with a cyanating agent.

[9] The production method according to claim 8, wherein the cyanation reaction is performed in a solvent.

[10] The production method according to claim 8, wherein the reaction temperature is 20 200 ° C.

[11] Formula (4) in the presence of a base:

In the formula, R ¹ represents a hydrogen atom or a hydrocarbon group,

And a 4_-unsubstituted-4-cyanotetrahydropyrani conjugate represented by the formula (5):

R ² X (5) In the formula, R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent, and X represents a leaving group.

Wherein a reaction reagent represented by the following formula is reacted:

A method for producing a 4-substituted-4-cyanotetrahydropyrani conjugate represented by the formula:

[12] The production method according to claim 11, wherein the reaction is carried out in a solvent.

13. The process according to claim 11, wherein the reaction temperature is −20 180 ° C.

[14] In the presence of an acid or a base, a compound of the formula (6):

In the formula, R ¹ represents a hydrogen atom or a hydrocarbon group, X represents a leaving group, and is characterized by reacting a 4_-substituted tetrahydropyran compound represented by Four) :

Wherein R ¹ is as defined above,

A method for producing a 4_unsubstituted-4-cyanotetrahydropyrani conjugate represented by the formula:

[15] The production method according to claim 14, wherein the reaction is carried out in a solvent.

[16] The process according to claim 14, wherein the reaction temperature is 20 200 ° C.

[17] cyanating agent power lithium cyanide, sodium cyanide, potassium cyanide, cyanide copper

15. The process according to claim 14, wherein the process is at least one selected from the group consisting of iron cyanide and cyanide-tetraethylammonium. 15. The process according to claim 14, wherein the cyanating agent is used in an amount of 1.0 to 10 mol per 1 mol of the 4-substituted tetrahydropyran compound.