JP2001192380A - Ester and method for synthesizing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for readily and efficiently producing an ester of 3-oxopentanedicarboxylic acid, and further to provide an intermediate usable for the production method. SOLUTION: A 6-halomethyl-4H-1,3-dioxin-4-one derivative is reacted with carbon monoxide and an alcohol or water to provide a 6-alkoxycarbonylmethyl-4 H-1,3-dioxin-4-one derivative, and the resultant derivative is further reacted with the alcohol or the water to provide the objective ester of 3- oxopentanedicarboxylic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a 6-alkoxycarbonylmethyl-4H-1,3-dioxin-4-one derivative, a method for producing the same, an intermediate which is important in the production process, and a method using the derivative. -Oxopentanedicarboxylic acid esters.

[0002]

2. Description of the Related Art 3-oxopentanedicarboxylic acid esters are compounds useful as fine chemical intermediates for pharmaceuticals, agricultural chemicals and the like, and as raw materials for polyesters.

As a method for synthesizing this compound, for example, Organic Synthesis Collective Volume 1
Volume 10 and Volume 237 disclose a method of treating citric acid with fuming sulfuric acid to produce acetone dicarboxylic acid and esterifying the dicarboxylic acid to obtain 3-oxopentanedicarboxylic acid. . However, in this method, acetone dicarboxylic acid as an intermediate is unstable and easily decomposed by heat, acid, alkali or the like. Therefore, particularly when industrially implemented, the target compound 3-
Low yield and selectivity of oxopentanedicarboxylic acid esters.

[0004] Japanese Patent Publication No. 3-24461 and Japanese Unexamined Patent Publication No. Sho 5
No. 9-78146 reports a method of synthesizing 3-oxopentanedicarboxylic acid from diketene, alkyl nitrite and carbon monoxide using a palladium catalyst. However, in order to obtain an alkyl nitrite, it is usually necessary to react an alcohol or water with nitrogen oxides requiring careful handling of nitric oxide, nitrogen dioxide, nitrous oxide, nitrous oxide and the like. Yes, lowers workability and reaction operability.

Therefore, these methods are not advantageous from the viewpoint of industrial implementation. Further, these methods cannot essentially synthesize an asymmetric diester (ie, a diester having a structure in which the alkoxy portions of the two ester groups are different), and even if synthesized, as a mixture with a symmetric diester. Can only be generated.

[0006] Swiss Patent 609,060 discloses a method using acetoacetate and chloroformate as raw materials. However, this method uses liquid ammonia and sodium amide, which are not always easy to handle industrially, and therefore cannot be said to be an advantageous method from the viewpoint of industrial production.

On the other hand, Chemistry Letters, June 1990
Vol. 901-904, Journal of Organic Chemistry 62:21, 7114 (1997)
Describe a ring opening reaction of 6-substituted-4H-1,3-dioxin-4-one with alcohol or water.

[0008] Also, Masanobu Higatai and Masaru Ichikawa, "Chemistry Seminar 11, Introduction to Homogeneous Catalysts and Heterogeneous Catalysts-Catalytic Chemistry in the Future-" Maruzen Co., Ltd. (1983), p.
It is described that an ester is synthesized by a carbonylation reaction of an aryl halide using a palladium catalyst.

However, there is no description about 6-alkoxycarbonylmethyl-4H-1,3-dioxin-4-one, and these reaction systems are referred to as 6-alkoxycarbonylmethyl-4H-1,3-dioxin-4-one. There is no example applied to.

[0010]

Accordingly, an object of the present invention is to provide a method for producing 3-oxopentanedicarboxylic acid ester industrially advantageously (for example, inexpensively and safely) and an intermediate used in the method. To provide.

It is another object of the present invention to provide a method for efficiently producing an asymmetrical 3-oxopentanedicarboxylic acid ester and an intermediate used in the production method.

Still another object of the present invention is to provide a method for efficiently producing 3-oxopentanedicarboxylic acid ester and an intermediate used in the method.

[0013]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, by reacting a specific halogen compound with carbon monoxide and an alcohol or water, a specific cyclic ester is formed. They have found that they can be efficiently synthesized, and that 3-oxopentanedicarboxylic acid esters can be industrially advantageously produced from this cyclic ester, and have completed the present invention.

That is, the cyclic ester of the present invention is represented by the following formula (1).

[0015]

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(Wherein, R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a chain aliphatic hydrocarbon group or a cyclic aliphatic hydrocarbon group, wherein the aliphatic hydrocarbon group is In the formula (1), R ¹ represents a linear or branched C _1-6 alkyl group, C _3-10 cycloalkyl group, or C _6-10 aryl- It may be a C _1-4 alkyl group, and R ² and R ³ may be the same or different and may be a hydrogen atom or a C _1-4 alkyl group.

Further, the present invention provides a method for producing the above cyclic ester, comprising the step of reacting a halogen compound represented by the following formula (2) with carbon monoxide and an alcohol or water represented by the following formula (3). Manufacturing methods are also included.

[0018]

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(Wherein X is a halogen atom, R ¹ ,
R ² and R ³ are the same as in the above formula (1). This production method is carried out in the presence of a catalyst (single platinum group metal or a compound containing a platinum group metal) composed of a platinum group metal (such as palladium). May be allowed to react.

Further, the present invention provides the above-mentioned cyclic ester,
A method for producing a dicarboxylic acid ester represented by the following formula (5) including a step of reacting with an alcohol or water represented by the following formula (4) is also included.

[0021]

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(Wherein, R ⁴ represents a hydrogen atom, a chain aliphatic hydrocarbon group, or a cyclic aliphatic hydrocarbon group, and the aliphatic hydrocarbon group may be further substituted with a substituent.
^{1 to} R ³ are the same as described above. Further, the present invention also includes a halogen compound represented by the following formula (2) (particularly, a compound in which X is a bromine atom or an iodine atom). This compound is useful as an intermediate for producing the cyclic ester.

[0023]

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(Wherein X is a halogen atom, and R ² and R ³ are the same as in the above formula (1))

[0025]

BEST MODE FOR CARRYING OUT THE INVENTION [Cyclic ester] In the cyclic ester (6-alkoxycarbonylmethyl-4H-1,3-dioxin-4-one derivative) represented by the above formula (1), R ¹ , R ² and The chain aliphatic hydrocarbon group represented by R ³ includes a linear or branched hydrocarbon group, for example, an alkyl group, an alkenyl group, an alkynyl group, and the like. The cyclic aliphatic hydrocarbon group (alicyclic hydrocarbon group) includes a saturated or unsaturated cyclic aliphatic hydrocarbon group, for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group and the like.

Examples of the alkyl group include a methyl group,
Ethyl, propyl, isopropyl, butyl, i
Straight or branched chain such as sobutyl group and tertiary butyl group
Condition C _1-10An alkyl group (preferably C_1-6Alkyl group, special
To C_1-4Alkyl group) and the like.

Examples of the alkenyl group include a vinyl group, an allyl group, an isopropenyl group, a 1-butenyl group,
A straight-chain or branched-chain C _2-6 alkenyl group (especially a C _2-4 alkenyl group) such as -butenyl group;

Examples of the alkynyl group include linear or branched C _2-6 alkynyl groups (especially C _2-4 alkynyl groups) such as ethynyl, propynyl, 1-butynyl and 2-butynyl. Can be exemplified.

Examples of the cycloalkyl group include a C _3-10 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cyclooctyl group, preferably a C _4-8 cycloalkyl group (particularly a C _4-8 cycloalkyl group).
_4-6 cycloalkyl group) and the like.

Examples of the cycloalkenyl group include C.sub.2 such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclooctenyl and the like.
Examples thereof include a _3-10 cycloalkenyl group, preferably a C _4-8 cycloalkenyl group (particularly, a C _4-6 cycloalkenyl group).

Examples of the cycloalkynyl group include C.sub.1 such as cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl, cyclooctynyl and the like.
Examples thereof include a _3-10 cycloalkynyl group, preferably a C _4-8 cycloalkynyl group (particularly, a C _4-6 cycloalkynyl group).

The aliphatic hydrocarbon group may have a substituent. Examples of such a substituent include a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom; a C _1-4 alkyl group such as a methyl group and an ethyl group; an acyl group [a C _1-4 alkyl-carbonyl group such as an acetyl group. ; C _6-10 aryl, such benzoyl group - such as a carbonyl group]; carbonyl group] -; - C _6-10 aryl, such as benzoyloxy group carbonyloxy group C _1-4 alkyl such as acyloxy groups [acetyloxy group An alkoxy group such as a methoxy group and an ethoxy group (C _1-4 alkoxy group and the like); an alkoxycarbonyl group such as a methoxycarbonyl group (C
_C1-4 alkoxy - carbonyl group); an aryloxy group such as phenoxy group can be exemplified.

In a preferred embodiment, the chain or cyclic hydrocarbon group may be substituted with an aromatic group, for example, a homocyclic group (aryl group) or a heterocyclic group (aromatic heterocyclic group). As the aryl group among the aromatic groups, a phenyl group,
Examples thereof include a C _6-10 aryl group such as a naphthyl group. Examples of the aromatic heterocyclic group include a group having at least one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
Examples thereof include a to 8-membered ring group, for example, a pyridinyl group, a piperidyl group, a furfuryl group, and the like. Examples of the aliphatic hydrocarbon group substituted with an aromatic group include an arylalkyl group (for example, a C _6-10 aryl-C _1-4 alkyl group such as a benzyl group and a phenethyl group) and an arylalkenyl group (for example, a C _{6 -10} aryl-C _2-4 alkenyl group), arylalkynyl group (for example, C _6-10 aryl-C _2-4 alkynyl group) and the like. These aromatic groups may be substituted with a suitable substituent. Suitable substituents include a halogen atom such as a chlorine atom, a bromine atom and a fluorine atom, an alkyl group (C
_A ketone group (C _1-6 alkylcarbonyl group such as methylcarbonyl group, ethylcarbonyl group, C _6-10 aryl-carbonyl group such as phenylcarbonyl group), an alkoxy group (methoxy group, A C _1-6 alkoxy group such as an ethoxy group, a propoxy group or a butoxy group; an aryloxy group (such as a phenoxyl group); an ester group (a C _1-6 alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group); Aryloxycarbonyl group such as a carbonyl group).

R ² and R ³ are bonded to each other to form a ring (eg, a C _3-6 cycloalkane ring, a 5- to 10-membered heterocyclic ring, etc.)
May be formed.

Desirable R ¹ is a linear or branched alkyl group (eg, a C _1-6 alkyl group such as a methyl group, an ethyl group, an isopropyl group, a t-butyl group), a cycloalkyl group (eg, A C _3-10 cycloalkyl group, particularly a C _5-8 cycloalkyl group such as a cyclohexyl group, or an aralkyl group (eg, a benzyl group, a phenethyl group, etc.
_6-10 aryl-C _1-4 alkyl group, especially phenyl-C _1-4
R ² and R ³ are preferably a hydrogen atom or an alkyl group (for example, a C _1-4 alkyl group, particularly a C _1-2 alkyl group such as a methyl group).

As such a cyclic ester (1),
For example, 6-C _1-4 alkoxy-carbonylmethyl-
2,2-diC _1-4 alkyl-4H-1,3-dioxin-4-one (for example, 6-methoxycarbonylmethyl-
2,2-dimethyl-4H-1,3-dioxin-4-one, 6-ethoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one, 6-isopropoxycarbonylmethyl-2 , 2-Dimethyl-4H-
1,3-dioxin-4-one, 6-t-butoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one, etc.); 6- _{C3-10cycloalkyloxy} -carbonylmethyl -2,2-diC _1-4 alkyl-
4H-1,3-dioxin-4-one (for example, 6-cyclohexyloxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one and the like);
C _6-10 aryl-C _1-4 alkyloxy-carbonylmethyl-2,2-diC _1-4 alkyl-4H-1,3-dioxin-4-one (for example, 6-benzyloxycarbonylmethyl-2, 2-dimethyl-4H-1,3-dioxin-4-one) and the like.

[Method for Producing Cyclic Ester] The cyclic ester (1) is obtained by mixing a halogen compound represented by the following formula (2) with carbon monoxide and an alcohol or water represented by the following formula (3) (particularly, alcohol) ) Can be produced by reacting

[0038]

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In the halogen compound (2), examples of X include halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among these halogen atoms, a bromine atom or an iodine atom (particularly an iodine atom) is preferable. The halogen compound (2) is useful as an intermediate for producing the cyclic ester (1).

Depending on the type of alcohol, among the compounds represented by the formula (2), it is preferable to use a compound in which X is a bromine atom or an iodine atom (particularly, an iodine atom).
Other halogen compounds (for example, 6-chloromethyl-4H
-1,3-dioxin-4one), the reaction may proceed more quickly.

Compounds wherein X is an iodine atom or a bromine atom (6-iodomethyl-4H-1,3-dioxin-4-
ON and 6-bromomethyl-4H-1,3-dioxin-
4-one) may be synthesized in advance and used, or a compound in which X is an iodine atom or a bromine atom (6-iodomethyl-4H-1,3-dioxin-4-one or 6-bromomethyl) in the reaction system. -4H-1,3-dioxin-4-one) may be used. When X is a fluorine atom, a chlorine atom, or the like, an iodizing agent or a brominating agent may be added to the reaction system to convert X into an iodine atom or a bromine atom. The iodinating agents include iodine, alkali metal iodides (such as lithium iodide, potassium iodide, and sodium iodide), and the brominating agents include bromine and alkali metal bromides (lithium bromide, potassium bromide). , Sodium bromide, etc.). For example, 6-chloromethyl-
4H-1,3-dioxin-4-one, iodide salts such as potassium iodide and sodium iodide, iodine, and the like are added to the system, and 6-iodomethyl-4H-1,3-dioxin-4 is added in the system. -ON or the like may be generated.

The iodinating agent or brominating agent may be used in an equimolar amount or a catalytic amount with respect to 1 mol of the halogen compound in which X is chlorine or fluorine. The amount of the iodinating agent or the brominating agent is usually 0.001 to 0.8 mol, preferably 0.01 mol, per 1 mol of the halogen compound.
05-0.3 mol, more preferably 0.01-0.2
It is about a mole.

The ratio of the amount of the halogen compound (2) used as the starting material to the amount of the alcohol or water is determined in consideration of the desired degree of progress of the reaction, economic reasons, and the type of reaction employed. Usually, the amount of the alcohol or water used is 0.1 to 10 with respect to 1 mol of the halogen compound (2).
The range is about 0000 mol, preferably about 0.5 to 1000 mol, and more preferably about 0.8 to 100 mol. The reaction may be performed using alcohol or water as a solvent.

The amount of carbon monoxide to be used is 1 mol or more (for example, 1 to 10 mol) per 1 mol of the halogen compound (2).
000 mol, preferably about 1 to 1000 mol, and more preferably about 1 to 100 mol).
Usually, it is performed in an atmosphere containing carbon monoxide.

The reaction with carbon monoxide is preferably carried out in the presence of a carbonylation catalyst, for example, a catalyst composed of a platinum group metal.

Examples of the platinum group metal used as a catalyst include platinum group metals described in J. D. Lee, translated by Hiroshi Hamaguchi and H. Sugano, "Inorganic Chemistry", Tokyo Kagaku Dojin (1982), p. Examples include Group 8 metals (eg, iron, ruthenium, osmium, etc.), Group 9 metals (eg, cobalt, rhodium, iridium, etc.), and Group 10 metals (eg, nickel, palladium, platinum, etc.). In the catalyst, these metals may be used alone or in combination of two or more. Of these metals, Group 10 metals (particularly palladium) are preferred.

The catalyst may be composed of a platinum group metal, and may be used alone or as a compound containing a metal element. Examples of the compound containing a platinum group metal include a metal salt, for example, an inorganic acid salt [eg, a hydrochloride, a sulfate, a nitrate, a salt with carbonic acid (carbonate, hydrogencarbonate, etc.), a salt with phosphoric acid (phosphoric acid) Salt, hydrogen phosphate, dihydrogen phosphate, etc.), boric acid salt, etc.], organic acid salt (for example, formate,
Salts of carboxylic acids such as acetates, lactates, oxalates, etc.),
Examples include halides (eg, chlorides, bromides, etc.), complexes of these metal components or salts thereof with ligands (eg, tetrakistriphenylphosphine palladium (0)), and the like. Examples of the ligand include phosphorus compounds such as phosphine (for example, trialkylphosphine such as tributylphosphine, tricycloalkylphosphine such as tricyclohexylphosphine, and triarylphosphine such as triphenylphosphine), nitrile, OH (hydroxo), and alkoxy. Groups (such as methoxy and ethoxy groups), acyl groups (such as acetyl and propionyl groups), alkoxycarbonyl groups (such as methoxycarbonyl groups and ethoxycarbonyl groups), acetylacetonato, cyclopentadienyl groups, halogen atoms, CO and H
₂ O (aqua), nitrogen-containing compounds (eg, NH ₃ , N
O ₂ , NO ₃ , alkylenediamine, pyridine and the like).

The valence of the metal of the catalyst (platinum group metal component) is not particularly limited, and is usually about 0 to 4, preferably about 0 to 2. The catalyst may be homogeneous or heterogeneous. In addition, the catalyst component is a suitable carrier (for example,
It can also be used as a solid catalyst in the form of being supported on activated carbon, silica (silica gel), alumina, zeolite, bentonite or other porous carrier). These catalysts can be used alone or in combination of two or more.

Taking the palladium catalyst as an example,
Catalysts include palladium nitrate, palladium chloride, palladium acetate, acetylacetonato palladium (II), tetraamminepalladium (II) chloride, bis (ethylenediamine) palladium (II) chloride, tetrachloropalladium
Potassium (II) acid, potassium tetranitropalladium (II), dichlorobis (trialkylphosphine) palladium (II), dimethylbis (triethylphosphine) palladium (II), biscyclopentadienylpalladium (II),
Tricarbonylcyclopentadienyl palladium (I),
Dichloro-μ-bis [bis (dimethylphosphino) methane] dipalladium (I), tetrakis (triphenylphosphine) palladium (0), bis (tricyclohexylphosphine) palladium (0), tetrakis (triethylphosphito) palladium ( 0), carbonyltris (triphenylphosphine) palladium (0), bis (cycloocta-1,5-diene) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like.

The amount of the catalyst used is not particularly limited.
0.001 to 1 mol, preferably 0.003 to 0.5 mol, more preferably 0.005 to 0.5 mol (for example, 0.01 to 0.5 mol) per 1 mol of the halogen compound (2).
2 mol).

As the reaction proceeds, halogen acid is generated in the reaction system. To neutralize the halogen acid, a base may be added to the reaction system. Examples of the base include inorganic bases such as alkali metal hydroxides (eg, sodium hydroxide and potassium hydroxide), alkali metal carbonates (eg, sodium carbonate, potassium carbonate, etc.), and alkali metal bicarbonates (eg, hydrogen carbonate). Sodium, potassium bicarbonate, etc.),
Alkaline earth metal hydroxide (calcium hydroxide, magnesium hydroxide, etc.), alkaline earth metal carbonate (eg, magnesium carbonate, calcium carbonate, etc.), alkaline earth metal bicarbonate (eg, magnesium bicarbonate) Organic bases or amines, for example, alkylamines (for example, tertiary amines such as tri-C _1-4 alkylamine such as triethylamine), and heterocyclic amines (for example, pyridine and the like). ), C
_1-4 alkyl anilines (eg, tertiary amines such as N, N-dimethylaniline); alkali metal carboxylate (eg, sodium acetate, potassium acetate, etc.), alkaline earth metal carboxylate (eg, , Magnesium acetate, calcium acetate, etc.). These bases can be used alone or in combination of two or more. Note that the use of an organic base or amines (for example, tertiary amines) seems to improve the selectivity.

In the reaction, a solvent may be used. When a solvent is used, there is no particular limitation as long as it does not hinder the progress of the reaction and dissolves the reaction components. As the solvent,
For example, acetone, ketones such as methyl ethyl ketone,
Ethers such as tetrahydrofuran and dioxane; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; aliphatic hydrocarbons such as pentane and hexane; aromatic hydrocarbons such as benzene and toluene; Examples thereof include halogen-containing compounds such as methylene, chloroform, bromoform, chlorobenzene, and bromobenzene. When an alcohol (eg, methanol, ethanol, tertiary butanol, etc.) is used as the solvent, it is preferable that the raw material alcohol itself is used as the solvent. These solvents are
They can be used alone or in combination of two or more. The amount of the solvent used is not particularly limited as long as the reaction components (such as a halogen compound) can be sufficiently dissolved.

The reaction is usually carried out at normal pressure to 500 atm (about 50 MPa), preferably at normal pressure to 100 atm (about 10 M).
Pa), more preferably at about normal pressure to 50 atm (for example, normal pressure to 10 atm (about 1 MPa)). In addition,
The reaction may be performed under reduced pressure for reasons of equipment or operation. The reaction is carried out under pressure (for example, 2 to 50 atm (about 0.2 to 5 MPa), preferably 5 to 30 atm (about 0.
5-3 MPa)), the selectivity seems to be improved.

The carbon monoxide may be pure carbon monoxide gas, or may be used as a mixed gas with an inert gas (nitrogen, argon, helium, etc.). That is, in addition to carbon monoxide in the gas phase, an inert gas, for example,
Nitrogen, argon, helium and the like may be present. Also,
The method for dissolving the gas component in the liquid phase is not particularly limited. In the reaction, carbon monoxide may be brought into contact with the reaction components,
If it can be sufficiently dissolved, it may be dissolved by gas-liquid contact, or, for example, a gas containing carbon monoxide may be blown into the liquid phase by a blowing pipe.

Further, the reaction temperature is determined under the reaction conditions.
There is no particular limitation as long as it is not lower than the melting point of the reaction system and not higher than the boiling point.
The reaction temperature is -30C to 200C, preferably -10C to
It is about 100 ° C. This reaction can be carried out by any of a batch system, a semi-batch system and a continuous system.

In the above cyclic ester, the compound (carboxylic acid) in which R ¹ is a hydrogen atom is reacted with an alcohol and then subjected to ordinary ester hydrolysis,
It may be produced by removing an alcohol-derived alkyl group by hydrolysis.

After completion of the reaction, the product is separated and purified by conventional means such as filtration, concentration, distillation, extraction, crystallization, recrystallization,
Separation and purification can be easily performed by means of separation and purification such as adsorption and column chromatography, or a combination thereof.

[Production method of dicarboxylic acid ester] The dicarboxylic acid ester (3-oxopentanedicarboxylic acid ester) represented by the following formula (5) is represented by the cyclic ester (1) and the following formula (4). And water (particularly alcohol).

[0059]

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(Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are each a hydrogen atom, a linear or branched aliphatic hydrocarbon group, or a saturated or unsaturated cyclic aliphatic group) Represents an aliphatic hydrocarbon group, and the aliphatic hydrocarbon group may be further substituted with an aromatic group.) A linear aliphatic hydrocarbon group represented by R ¹ , R ² , R ³ and R ⁴ , Examples of the aliphatic hydrocarbon group and / or the aromatic group which these aliphatic hydrocarbon groups may have include the groups exemplified in the above-mentioned R ^{1 to} R ³ . Preferred R ⁴ is a hydrogen atom, a C _1-10 aliphatic hydrocarbon group (eg, a C _1-6 alkyl group such as a methyl group or an ethyl group, particularly a C _1-4 alkyl group), or a C _4-8 alicyclic group. And hydrocarbon groups.

In this method, the cyclic ester is not limited to the method for producing the cyclic ester of the present invention, but may be prepared by another method.

The ratio between the cyclic ester used as the starting material and the alcohol or water is determined in consideration of the intended progress of the reaction, economic reasons, and the type of reaction employed.
Usually, the amount of the alcohol or water used is 0.1 to 100000 mol, preferably 0.1 to 100 mol per mol of the cyclic ester.
It is in the range of about 5 to 1000 mol, more preferably about 0.8 to 100 mol. In the reaction, alcohol or water may be used as a solvent.

This reaction proceeds only by heating the reaction system. However, when promoting the progress of the reaction, a catalyst may be used. Examples of the catalyst include inorganic acids (sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, etc.), organic acids (sulfonic acids, for example, C _1-6 alkanesulfonic acid such as methanesulfonic acid, ethanesulfonic acid, etc., paratoluenesulfonic acid, benzenesulfonic acid). Aromatic sulfonic acids such as acids; organic carboxylic acids such as acetic acid, C _1-10 saturated or unsaturated mono- or polycarboxylic acids such as propionic acid; halogenated organic acids such as trichloroacetic acid, trifluoroacetic acid and the like. halogenated carboxylic acids; halogenated alkanesulfonic acids such as trifluoromethanesulfonic acid), solid acid [sulfates (calcium sulfate, etc.), metal oxides (such as _{SiO 2, Al 2 O 3)} , having a zeolite (acidic OH Y-type, X-type, A-type zeolite, etc.), heteropolyacid, ion-exchange resin (H
Cation exchange resin such as a mold)]]. These catalysts can be used alone or in combination of two or more.

The amount of the catalyst to be used is not particularly limited, and is preferably 0.001 to 1 mol, preferably 0.005 to 0.5 mol, more preferably 0.01 to 1 mol, per mol of the cyclic ester.
It is about 0.2 mol.

In the reaction, a solvent may be used. When a solvent is used, there is no particular limitation as long as it does not hinder the progress of the reaction and dissolves the reaction components. As the solvent,
The same solvent as the solvent used for producing the cyclic ester can be used.

This reaction is usually carried out at normal pressure. The reaction may be performed under reduced pressure or increased pressure for reasons of equipment or operation.

The reaction temperature may be at least the melting point of the reaction system and at most the boiling point under the reaction conditions. Reaction temperature is -30 ° C
To 300 ° C, preferably about -10 ° C to 200 ° C. This reaction may be any of a batch system, a semi-batch system and a continuous system.

In the case of producing a derivative of the dicarboxylic acid ester represented by the above formula (5), wherein R ¹ and / or R ⁴ is a hydrogen atom, the reaction is carried out using an alcohol and then a normal ester is obtained. By performing hydrolysis, an alkyl group derived from alcohol can be removed by hydrolysis.

The product can be isolated in the same manner as in the production of the cyclic ester.

When the production of the cyclic ester and the production of the dicarboxylic acid ester are carried out continuously, the cyclic ester obtained in the former reaction can be isolated and used in the latter reaction. Alternatively, the cyclic ester generated in the reaction system can be directly used for the latter reaction without separation and purification.

[0071]

According to the present invention, 3-oxopentanedicarboxylic acid esters can be efficiently synthesized under mild reaction conditions using only compounds which are relatively easy to obtain and handle, or New compound 6
-Alkoxycarbonylmethyl-4H-1,3-dioxin-4-one can be synthesized. Further, 3-oxopentanedicarboxylic acid esters having an asymmetric structure as well as a symmetric structure can be easily synthesized.

[0072]

EXAMPLES The present invention will be described below in more detail with reference to Examples, but the present invention is not limited to these Examples. In the following examples, the methyl group is M
e, ethyl group is Et, isopropyl group is i-Pr, tertiary butyl group is t-Bu, benzyl group is PhC
H ₂ and cyclohexyl may be abbreviated as c-Hex, trimethylsilane as TMS, and tetrahydrofuran as THF.

The IR spectrum was obtained from PERKIN-ELM.
The measurement was performed using ER 1600 Series FT-IR.

The NMR spectrum was obtained from BRUKER AM
500, 500 MHz ( ¹ H-NMR) or 12 MHz
It was measured at 5.7 MHz ( ¹³ C-NMR) using TMS as an internal standard.

The MS spectrum was measured by ThermoQuest L
Using CQ, syringe method, ionization mode APCI,
It was measured by detecting positive ions.

Example 1 6-Iodomethyl-2,2-dimethyl-4H-1,3-
Synthesis of dioxin-4-one 2.16 g of sodium iodide was dissolved in 16 mL of acetone, and 2,2-dimethyl-6 diluted with 4 mL of acetone was used.
-Chloromethyl-1,3-dioxin-4-one 2.0
After adding 0 g, the mixture was stirred at room temperature for 2 hours. Insoluble matters were removed by filtration from the reaction solution, and the filtrate was concentrated. The residue was dissolved in 20 mL of chloroform, the insolubles were removed by filtration again, and the filtrate was concentrated. The obtained residue is subjected to silica gel column chromatography (solvent: hexane / ethyl acetate =
1/1 (volume ratio)) to give 6-iodomethyl-
2.65 g of 2,2-dimethyl-4H-1,3-dioxin-4-one was obtained as a yellow liquid. N of this compound
The MR spectrum is shown below.

¹ H-NMR (CD ₃ Cl) ppm: 1.7
1 (s, 6H, Me), 3.83 (s, 2H, CH
_{2 I), 5.52 (s,} 1H, = CH).

Example 2 6-methoxycarbonylmethyl-2,2-dimethyl-4
Synthesis of H-1,3-dioxin-4-one (synthesis from 6-iodomethyl-2,2-dimethyl-4H-1,3-dioxin-4-one) Palladium chloride was placed in a 50 mL two-necked flask. .1
00g (0.564 mmol), potassium carbonate 0.78
2 g (5.66 mmol), potassium iodide 0.940
g (5.66 mmol) was introduced, and carbon monoxide was introduced by a balloon (atmospheric pressure) to make the system a carbon monoxide atmosphere.
10 mL of methanol, 6-chloromethyl-2,
1.0 g (5.66 mmol) of 2-dimethyl-4H-1,3-dioxin-4-one was added, and the mixture was stirred at room temperature for 18 hours.

After completion of the reaction, the reaction mixture was filtered, and the obtained filtrate was concentrated. 25 mL of ethyl acetate and 25 mL of water
mL and mixed, and separated into two layers. The upper layer (organic layer) was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 0.408 g of a black-brown residue.

The residue was confirmed by ¹ H-NMR. 6-methoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one and 2,2,6
-Trimethyl-4H-1,3-dioxin-4-one was detected at a molar ratio of 1.0: 1.3. Starting materials, 6-chloromethyl-2,2-dimethyl-4H-1,
No remaining 3-dioxin-4-one could be confirmed, and almost no other products were present.

This mixture was purified by silica gel thin layer chromatography (mobile layer: hexane / ethyl acetate = 2/1 (volume ratio)) to give the desired 6-methoxycarbonylmethyl-2,2-dimethyl-4H-1. , 3-Dioxin-4-one 68.1 mg. The Rf value was 0.25. The IR spectrum, NMR spectrum and MS spectrum of this compound are shown below.

IR (neat): 3000, 2956,
^{1732,1643 cm -1 1 H-NMR (} CD 3 Cl) ppm: 1.71 (s, 6
H, CMe ₂ ), 3.29 (s, 2H, CH ₂ CO),
3.75 (s, 3H, COOMe), 5.40 (s, 1
^{H, CH = C) 13 C} -NMR (CDCl 3) ppm: 24.9 (CM
_{e 2), 39.2 (C H} 2 CO), 52.5 (OMe),
96.5 (HC =), 107.3 (Me ₂ C ), 16
_{0.7 (O = CCH 2 C =} ), 163.7 (C OOM
e), 167.6 (= C- C O-O-CMe 2 -) CI-MS (m / z): 201 (M + +1,100
^{%), 143 (M + +} 1-58).

Example 3 6-methoxycarbonylmethyl-2,2-dimethyl-4
Synthesis of H-1,3-dioxin-4-one (synthesis from 6-chloromethyl-2,2-dimethyl-4H-1,3-dioxin-4-one) Except that potassium iodide was not used, The reaction was carried out as in Example 2. The reaction mixture was worked up as above to give 0.500 g of residue. When this residue was confirmed by ¹ H-NMR, 6-methoxycarbonylmethyl-2,2
-Dimethyl-4H-1,3-dioxin-4-one and 2,2,6-trimethyl-4H-1,3-dioxin-
4-one was detected at a molar ratio of 1.0: 3.0.

Example 4 6-methoxycarbonylmethyl-2,2-dimethyl-4
Synthesis of H-1.3-dioxin-4-one (change of catalytic palladium species) Except that 0.130 g (0.579 mmol) of palladium acetate was used as a catalyst instead of palladium chloride, and potassium iodide was not used. The reaction was carried out as in Example 2. The reaction mixture was worked up as described above and a residue of 0.42
8 g were obtained. When this residue was confirmed by ¹ H-NMR, 6-methoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one and 2,2,6
-Trimethyl-4H-1,3-dioxan-4-one was detected at a molar ratio of 1.0: 9.0.

Example 5 Synthesis of 6-isopropoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one The procedure of Example 2 was repeated except that 10 mL of isopropyl alcohol was used instead of methanol as the alcohol. The reaction was performed similarly. The reaction mixture was treated in the same manner as above, and the organic layer obtained by the liquid separation operation was dried and concentrated to give almost pure 6-isopropoxycarbonylmethyl-2,2-.
Dimethyl-4H-1,3-dioxin-4-one 0.9
99 g were obtained. 6-isopropoxycarbonylmethyl-
The yield of 2,2-dimethyl-4H-1,3-dioxin-4-one is based on the starting material 6-chloromethyl-2,2-dimethyl4H-1,3-dioxin-4-one. It was 74 mol%. The NMR spectrum data of this compound is shown below.

¹ H-NMR (CD ₃ Cl) ppm: 1.2
6 (d, J = 6.4 Hz, 6H, CH Me ₂ ), 1.7
1 (s, 6H, CMe ₂ ), 3.23 (s, 2H, CH ₂
CO), 5.0-5.1 (m, 1H , C H Me 2), 5.
38 (s, 1H, CH = C).

Other products are 2,2,6-trimethyl-4
H-1,3-dioxin-4-one is used as starting material 6-
Produced in a yield of 5.8 mol% based on chloromethyl-2,2-dimethyl-4H-1,3-dioxin-4-one, but starting material 6-chloromethyl-2,2-dimethyl- No residual 4H-1,3-dioxin-4-one could be confirmed.

Example 6 6-tert-butoxycarbonylmethyl-2,2-
Synthesis of dimethyl-4H-1,3-dioxin-4-one The reaction was carried out in the same manner as in Example 2, except that 10 mL of tertiary butyl alcohol was used instead of methanol as the alcohol. Treating the reaction mixture as above,
By drying and concentrating the organic layer obtained by the liquid separation operation, 6-tert-butoxycarbonylmethyl-2,
0.44 g of 2-dimethyl-4H-1,3-dioxin-4-one was obtained. The NMR spectrum data of this compound is shown below.

¹ H-NMR (CD ₃ Cl) ppm: 1.4
6 (s, 9H, t-Bu), 1.71 (s, 6H, CM
e ₂ ), 3.17 (s, 2H, CH ₂ CO), 5.36
(S, 1H, CH = C).

Other products are 2,2,6-trimethyl-4
H-1,3-dioxin-4-one. Starting materials, 6-chloromethyl-2,2-dimethyl-4H-1,
No remaining 3-dioxin-4-one could be confirmed.

Example 7 6-ethoxycarbonylmethyl-2,2-dimethyl-4
Synthesis of H-1,3-dioxin-4-one Ethanol instead of methanol as alcohol 10
The reaction was carried out in the same manner as in Example 2 except that mL was used.
The reaction mixture was treated in the same manner as above, and the organic layer obtained by the liquid separation operation was dried and concentrated to give 6-ethoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one. .70 g were obtained. NM of this compound
The R spectrum data is shown below.

[0092]¹H-NMR (CD_ThreeCl) ppm: 1.2
8 (t, J = 7.1 Hz, 3H,CH ₃ CH_Two) 1.7
1 (s, 6H, CMe_Two), 3.25 (s, 2H, CH_Two
CO), 4.20 (q, J = 7.1 Hz, 2H, CH_Three
CH ₂ ), 5.39 (s, 1H, CH = C).

Other products are 2,2,6-trimethyl-4
H-1,3-dioxin-4-one. Starting material 6-chloromethyl-2,2-dimethyl-4H-1,3-
No remaining dioxin-4-one could be confirmed.

Example 8 Synthesis of 6-benzyloxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one As an alcohol, 0.6 g of benzyl alcohol was used instead of methanol, and 10 mL of THF was used as a solvent. The reaction was carried out in the same manner as in Example 2, except for using. The reaction mixture was treated in the same manner as above, and the organic layer obtained by the liquid separation operation was dried and concentrated to give 6-benzyloxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one. 0.75 g was obtained. The NMR spectrum data of this compound is shown below. Starting material 6-chloromethyl-2,2-dimethyl-4H-1,3-dioxin-
No remaining 4-one could be confirmed.

¹ H-NMR (CD ₃ Cl) ppm: 1.6
3 (s, 6H, CMe ₂ ), 3.30 (s, 2H, CH ₂
CO), 5.16 (s, 2H , PhC H 2) 5.38
(S, 1H, CH = C), 7.3-7.5 (m, 5H,
Ph).

Example 9 6-Cyclohexyloxycarbonylmethyl-2,2-
Synthesis of dimethyl-4H-1,3-dioxin-4-one As an alcohol, 0.6 g of cyclohexanol was used instead of methanol, and acetonitrile 10 m was used as a solvent.
The reaction was carried out in the same manner as in Example 2 except that L was used. The reaction mixture is treated in the same manner as above, and the organic layer obtained by the liquid separation operation is dried and concentrated to give 6-cyclohexyloxycarbonylmethyl-2,2-dimethyl-4H-
0.92 g of 1,3-dioxin-4-one was obtained. The NMR spectrum data of this compound is shown below. Starting material 6-chloromethyl-2,2-dimethyl-4H-1,
No remaining 3-dioxin-4-one could be confirmed.

¹ H-NMR (CD ₃ Cl) ppm: 1.1
-2.0 (m, 10H, cyclohexane ring methylene), 1.71 (s, 6H, CMe 2), 3.24
_{(S, 2H, CH 2 CO} ), 4.8-4.9 (m, 1
_{H, OC H (CH 2)} 2), 5.38 (s, 1H, CH =
C).

The results of Examples 2 to 9 are summarized and are shown in Table 1.

[0099]

[Table 1]

In Table 1, the target compound was 6-alkoxycarbonylmethyl-2,2-dimethyl-4H-1,
3-dioxin-4-one;
6-trimethyl-4H-1,3-dioxin-4-one.

Example 10 Synthesis of tert-butylmethyl 3-oxopentanedicarboxylate 12 mL of chloroform was added to 6-methoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-
ON 51.7 mg (0.258 mmol), tertiary butyl alcohol 20.6 mg (0.277 mmol)
l) was dissolved and sealed in a sealed tube. This system is
After heating for an hour, the target tert-butylmethyl 3-oxopentanedicarboxylate was obtained in a yield of 81 mol%. The NMR spectrum data of this compound is shown below. No by-product was present, and the starting material 6-ethoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one was recovered.

¹ H-NMR (CD ₃ Cl) ppm: 1.4
7 (s, 9H, t-Bu), 3.51 (s, 2H, CH
₂ ), 3.61 (s, 2H, CH ₂ ), 3.74 (s, 3
H, Me).

Example 11 6-methoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4 under carbon monoxide pressurized condition
The reaction was carried out in the same manner as in Example 2 except that the amount of potassium iodide was 0.094 g (0.566 mmol), and the reaction system was a carbon monoxide atmosphere of 1 MPa, using a microbomb with a capacity of 100 mL. .

After the completion of the reaction, the reaction mixture was treated in the same manner as described above, and confirmed by ¹ H-NMR. 6-methoxycarbonylmethyl-2,2-dimethyl-4H-1,3
Dioxin-4-one and 2,2,6-trimethyl-4
H-1,3-dioxin-4-one has a molar ratio of 1.0:
Detection was possible at a rate of 0.52. No remaining 6-chloromethyl-2,2-dimethyl-4H-1,3-dioxin-4-one as a starting material could be confirmed, and almost no other products were present. The reaction proceeded efficiently even when the amount of potassium iodide was reduced, and the selectivity was improved by pressurizing the reaction (1 MPa).

Example 12 6-methoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4 under carbon monoxide pressurized condition
Synthesis of -one (use of amine) The reaction was carried out in the same manner as in Example 11 except that 1.2 g (11.8 mmol) of triethylamine was used instead of potassium carbonate as a base.

After the completion of the reaction, the reaction mixture was treated in the same manner as described above, and confirmed by ¹ H-NMR. 6-methoxycarbonylmethyl-2,2-dimethyl-4H-1,3
Dioxin-4-one and 2,2,6-trimethyl-4
H-1,3-dioxin-4-one has a molar ratio of 1.0:
It could be detected at a rate of 0.30. No remaining 6-chloromethyl-2,2-dimethyl-4H-1,3-dioxin-4-one as a starting material could be confirmed, and almost no other products were present. By using an organic base or an amine as the base, selectivity was improved.

Example 13 6-methoxycarbonylmethyl-2,2-dimethyl-4
Synthesis of H-1,3-dioxin-4-one (reduction of amount of Pd)
3.32 g (0.18 mmol), triethylamine
0 g (59.2 mmol), potassium iodide 0.470
g (2.83 mmol), methanol 25 mL, 6-chloromethyl-2,2-dimethyl-4H-1,3-dioxin-4-one 5.0 g (28.3 mmol) were added,
Stirred at room temperature for 22 hours.

After the completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated. 30 mL of ethyl acetate was added to the residue, and water 3
Washed twice with 0 mL. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 4.013 g of a black-brown residue.

The reaction mixture was analyzed by ¹ H-NMR to find that 6-methoxycarbonylmethyl-2,2-
Dimethyl-4H-1,3-dioxin-4-one and 2,
2,6-trimethyl-4H-1,3-dioxin-4-
ON was detected at a molar ratio of 1.0: 0.27. 6-chloromethyl-2,2-dimethyl-4 as starting material
No remaining H-1,3-dioxin-4-one could be confirmed, and almost no other products were present.

Example 14 6-methoxycarbonylmethyl-2,2-dimethyl-4
Synthesis of H-1,3-dioxin-4-one (reduction of Pd amount) A reaction was carried out in the same manner as in Example 13 except that 0.016 g (0.09 mmol) of palladium chloride was stirred at room temperature for 50 hours. Was.

After completion of the reaction, the reaction mixture was analyzed by ¹ H-NMR to find that 6-methoxycarbonylmethyl-
2,2-dimethyl-4H-1,3-dioxin-4-one and 2,2,6-trimethyl-4H-1,3-dioxin-4-one in a molar ratio of 1.0: 0.29. Could be detected. No remaining 6-chloromethyl-2,2-dimethyl-4H-1,3-dioxin-4-one as a starting material could be confirmed, and almost no other products were present.

Claims (15)

[Claims] 1. A cyclic ester represented by the following formula (1). Embedded image (Wherein, R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a chain aliphatic hydrocarbon group, or a cycloaliphatic hydrocarbon group, and the aliphatic hydrocarbon group may further have a substituent May be replaced by 2. In the formula (1), R ¹ is a linear or branched C _1-6 alkyl group, C _3-10 cycloalkyl group or C _6-10 aryl-C _1-4 alkyl group. Yes, R ² and R
The cyclic ester according to claim 1, wherein ³ is a hydrogen atom or a _C1-4 alkyl group. 3. The cyclic ester according to claim 1, wherein in formula (1), R ² and R ³ are methyl groups. 4. The production of a cyclic ester according to claim 1, comprising a step of reacting a halogen compound represented by the following formula (2) with carbon monoxide and an alcohol or water represented by the following formula (3). Method. Embedded image (Wherein X is a halogen atom, and R ² and R ³ are the same as in the above formula (1)) R ¹ —OH (3) (wherein, R ¹ is the same as the above formula (1)) ) 5. The method according to claim 4, wherein in the formula (2), X is an iodine atom or a bromine atom. 6. A compound comprising a halogen compound in which X is a fluorine atom or a chlorine atom in the formula (2), carbon monoxide and the alcohol or water, in the presence of at least one selected from an iodinating agent and a brominating agent. Claim 4
The manufacturing method as described. 7. The method according to claim 4, wherein the reaction is carried out in the presence of a catalyst composed of a platinum group metal. 8. The method according to claim 4, wherein the reaction is carried out in the presence of a catalyst composed of a Group 10 metal of the periodic table. 9. The method of claim 7, wherein the platinum group metal is palladium.
The manufacturing method as described. 10. The method according to claim 4, wherein the reaction is carried out in the presence of an inorganic base or an organic base. 11. The method according to claim 10, wherein the base is an amine. 12. The production method according to claim 4, wherein the reaction is performed under pressure. 13. A dicarboxylic acid ester represented by the following formula (5) is produced by reacting a cyclic ester represented by the following formula (1) with an alcohol or water represented by the following formula (4). Method. Embedded image (Wherein, R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a chain aliphatic hydrocarbon group, or a cycloaliphatic hydrocarbon group, and the aliphatic hydrocarbon group may further have a substituent R ⁴ —OH (4) wherein R ⁴ represents a hydrogen atom, a chain aliphatic hydrocarbon group, or a cyclic aliphatic hydrocarbon group, and the aliphatic hydrocarbon group is (It may be further substituted with a substituent.) (Wherein R ¹ and R ⁴ are the same as described above) 14. A halogen compound represented by the following formula (2). Embedded image (In the formula, X is a halogen atom, and R ² and R ³ are the same as in the above formula (1).) 15. The halogen compound according to claim 14, wherein X in the formula (2) is a bromine atom or an iodine atom.