JP2003313150A - Method for producing 1,3-cyclohexanedione compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a 1,3-cyclohexanedione compound by which the objective material is obtained by one step in high yield by using a mild reaction condition not requiring a high temperature and a high pressure. <P>SOLUTION: This method for producing the 1,3-cyclohexanedione compound involves hydrogenating a 1,3-dihydroxybenzene compound in the presence of (a) a hydrogenation catalyst and (b) a fluorine-containing organic acid. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing a 1,3-cyclohexanedione compound.

[0002]

BACKGROUND OF THE INVENTION 1,3-Cyclohexanedione and its substituted derivatives (hereinafter referred to as "1,3-cyclohexanedione compounds") are useful as intermediates for the production of various pharmaceuticals and agricultural chemicals.

Conventionally, as a method for producing a 1,3-cyclohexanedione compound, for example, a method of cyclizing (i) ethyl or methyl 5-oxyhexanoate in the presence of a base (German Patent No. 2,749) , 437, US Pat. No. 3,922,307, US Pat. No. 4,02.
No. 8,417), (ii) Resorcinol or its derivative (hereinafter referred to as “1,3-dihydroxybenzene compound”) under reduced pressure and alkaline conditions with Raney nickel (Organic).
Synthesis. , Coll. Vol. 3,27
8 pages, 1955, European Patent Application 331,422, European Patent Application 219,282, J. Chem. So
c. , 811, 1953, J. Am. Che
m. Soc. , 78, 4405, 1956, etc.) is known.

As another method, (iii) 1,3-
A method of hydrogenating a dihydroxybenzene compound with hydrogen gas in the presence of a noble metal catalyst under basic conditions (JA.
m. Chem. Soc. , 83, 2739) are also known.

However, these methods are 1,3-
The cyclohexanedione compound yield is low, undesired by-products are generated, a complicated purification step is required after the reaction is completed, and the reaction conditions are high temperature and high pressure. It wasn't what I should do.

As a method for solving these problems, JP-A-10-87548 discloses that a 1,3-dihydroxybenzene compound is added in the presence of a metal catalyst selected from the group consisting of platinum, palladium, rhodium and ruthenium. To the corresponding 1, by reducing with a hydrogen donor in a solvent.
A method for producing a 1,3-cyclohexanedione compound is described, which comprises producing a salt of a 3-diketone compound, and then neutralizing the salt of the diketone compound with an acid to convert into a corresponding 1,3-cyclohexanedione compound. ing. According to this method, the desired product can be obtained in high yield without requiring high pressure.

[0007]

However, the above-mentioned method has a drawback that an expensive hydrogen donor is used and that they are decomposed to generate a gas.

[0008] Therefore, the object of the present invention is to provide a method for producing a 1,3-cyclohexanedione compound which can obtain the desired product in a high yield in one step under mild reaction conditions which do not require high temperature and high pressure. And

[0009]

[Means for Solving the Problems] The present inventor diligently studied a reaction for hydrogenating a 1,3-dihydroxybenzene compound in the presence of a hydrogenation catalyst to obtain a corresponding 1,3-cyclohexanedione compound. . As a result, it was found that the presence of a fluorine-containing organic acid such as trifluoroacetic acid in the reaction system enables the desired 1,3-cyclohexanedione compound to be efficiently obtained in one step under mild reaction conditions. The invention was completed.

Thus, according to the present invention, 1,3-dihydroxybenzene compound is hydrogenated in the presence of (a) a hydrogenation catalyst and (b) a fluorine-containing organic acid. A method for producing a dione compound is provided.

In the present invention, the 1,3-dihydroxybenzene compound has the formula (1)

[0012]

[Chemical 3]

[Wherein R 1, R 2, R 3 and R 4 are
Each independently has a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, and a substituent. Optionally a phenyl group or the formula:-(C
H ₂ ) _n COOR5 (wherein, n is 0 or an integer of 1 to 6 and R 5 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms)], and the above 1,
The 3-cyclohexanedione compound has the formula (2)

[0014]

[Chemical 4]

The compound represented by the formula (wherein R1, R2, R3 and R4 have the same meanings as described above) or an enol type tautomer thereof is preferable. Further, in the production method of the present invention, it is preferable to use trifluoroacetic acid as the fluorine-containing organic acid.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The manufacturing method of the present invention will be described below.
(A) 1,3-dihydroxybenzene compound, (B) hydrogenation catalyst, (C) fluorine-containing organic acid, (D) hydrogenation reaction,
And (E) 1,3-cyclohexanedione compound will be described in detail.

(A) 1,3-Dihydroxybenzene Compound In the present invention, resorcinol having a hydroxy group at the 1,3-position of the benzene ring or its substituted derivative 1,3
-Using a dihydroxybenzene compound as a starting material. The 1,3-dihydroxybenzene compound used in the present invention is not particularly limited as long as it is a benzene compound having a hydroxyl group at the 1-position and 3-position of the benzene ring, but the compound represented by the formula (1) is preferable.

In the formula (1), R1, R2, R3 and R4
Are each independently a hydrogen atom; methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group,
Carbon number 1 to 1 such as isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, n-hexyl group
6 alkyl group; cycloalkyl group having 3 to 6 carbon atoms such as cyclopropyl group, cyclopentyl group, cyclohexyl group; methoxy group, ethoxy group, n-propoxy group,
Isopropoxy group, n-butoxy group, isobutoxy group,
1 to 1 carbon atoms such as sec-butoxy group, tert-butoxy group, n-pentyloxy group and n-hexyloxy group
6 alkoxy group; chloromethyl group, fluoromethyl group, bromomethyl group, dichloromethyl group, difluoromethyl group, trifluoromethyl group, trichloromethyl group,
A phenyl group which may have a substituent; 2,2,2-trifluoroethyl group, a haloalkyl group having 1 to 6 carbon atoms, such as pentafluoroethyl group or a group represented by the formula :-( _CH 2)
It represents a group represented by _n COOR5.

The substituent of the phenyl group which may have a substituent has 1 carbon atom such as methyl group and ethyl group.
An alkyl group having 6 to 6; an alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, an n-propoxy group and an isopropoxy group; Further, the phenyl group may have two or more substituents which are the same or different from each other at any position on the benzene ring.

In the group represented by the formula:-(CH ₂ ) _n COOR5, R5 is a hydrogen atom; or a methyl group,
It represents an alkyl group having 1 to 6 carbon atoms such as an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and a tert-butyl group. n is 0 or an integer of 1 to 6.

Specific examples of the group represented by the formula:-(CH ₂ ) _n COOR5 include carboxyl group; methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group. , An alkoxycarbonyl group such as a tert-butoxycarbonyl group; a carboxyalkyl group such as a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxypropyl group; a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a 2-methoxycarbonylethyl group, An alkoxycarbonylalkyl group such as a 3-methoxycarbonylpropyl group; and the like.

Specific examples of the 1,3-dihydroxybenzene compound represented by the above formula (1) include resorcinol; 1,3-dihydroxy-2-methylbenzene, 1,
3-dihydroxy-2-methoxybenzene, 1,3-dihydroxy-2-trifluoromethylbenzene, 1,3
-Dihydroxy-2-methoxycarbonylbenzene,
2-substituted-1,3-dihydroxybenzene compounds such as 2,6-dihydroxybenzoic acid, 2,6-dihydroxyphenylacetic acid and 1,3-dihydroxy-2-ethoxycarbonylmethylbenzene;

1,3-dihydroxy-4-methylbenzene, 1,3-dihydroxy-4-methoxybenzene,
1,3-dihydroxy-4-trifluoromethylbenzene, 1,3-dihydroxy-4-methoxycarbonylbenzene, 2,4-dihydroxybenzoic acid, 2,4-dihydroxyphenylacetic acid, 1,3-dihydroxy-4-ethoxy 4-substituted-1, such as carbonylmethylbenzene,
3-dihydroxybenzene compound;

1,3-dihydroxy-5-methylbenzene, 1,3-dihydroxy-5-methoxybenzene,
1,3-dihydroxy-5-trifluoromethylbenzene, 1,3-dihydroxy-5-methoxycarbonylbenzene, 3,5-dihydroxybenzoic acid, 3,5-dihydroxyphenylacetic acid, 1,3-dihydroxy-5-ethoxy 5-substituted-1, such as carbonylmethylbenzene,
3-dihydroxybenzene compound;

1,3-dihydroxy-4,5-dimethylbenzene, 1,3-dihydroxy-4-methoxy-5
4,5-Disubstituted-1,3-dihydroxybenzene compounds such as methylbenzene and 1,3-dihydroxy-4-trifluoromethyl-5-methylbenzene; 1,3-dihydroxy-2,4-dimethylbenzene, 1 , 3-dihydroxy-2-methoxy-4-methylbenzene, 1,3-
2,4-disubstituted-1,3-dihydroxybenzene compounds such as dihydroxy-2-trifluoromethyl-4-methylbenzene;

1,3-dihydroxy-2,5-dimethylbenzene, 1,3-dihydroxy-2-methoxy-5
2,5-Disubstituted-1,3-dihydroxybenzene compounds such as methylbenzene and 1,3-dihydroxy-2-trifluoromethyl-5-methylbenzene; 1,3-dihydroxy-4,5,6-trimethylbenzene Such as 4,
5,6-trisubstituted-1,3-dihydroxybenzene compound; and the like.

Of these, resorcinol or a mono-substituted 1,3-dihydroxybenzene compound is preferable from the viewpoint of easy availability and efficient production of the desired product.
Resorcinol is especially preferred.

(B) Hydrogenation catalyst The present invention is for carrying out hydrogenation in the presence of a hydrogenation catalyst. The hydrogenation catalyst is not particularly limited as long as it is stable to a fluorine-containing organic acid. As the hydrogenation catalyst, for example, a metal catalyst of Group 8 to 10 elements of the periodic table can be used.

Concretely, iron, cobalt, nickel, ruthenium, rhodium, which are elements of Groups 8 to 10 of the periodic table,
A metal catalyst containing a simple substance of a metal selected from the group consisting of palladium, osmium, iridium and platinum, or one or more compounds of the metal can be used. Examples of the metal compound include halides, sulfates and nitrates. These hydrogenation catalysts
Each may be used alone, or two or more kinds may be used in combination.

The metal catalyst is preferably supported on a carrier. The carrier is not particularly limited as long as it is stable to the hydrogenation reaction in the presence of a fluorine-containing organic acid. Examples of the carrier include carbon, alumina, silica, silica-alumina, clay, zeolite, titania and the like. The shape, size, etc. of the carrier are not particularly limited, and may be a powder, a spherical, or a pellet-shaped molded product.

The amount of the metal or metal compound supported on the carrier is usually 0.5 to 20% by weight, preferably 1 to 20% by weight when the carrier is powder, and 1 to 20% when the carrier is a molded product. 10% by weight is preferred. The amount of hydrogenation catalyst used is usually 0.001 to 50 parts by weight, preferably 0.01 to 20 parts by weight, based on 100 parts by weight of the 1,3-dihydroxybenzene compound.

(C) Fluorine-Containing Organic Acid In the present invention, hydrogenation is carried out in the presence of a fluorine-containing organic acid. By allowing the fluorinated organic acid to be present in the reaction system, the desired 1,3-cyclohexanedione compound can be obtained in a good yield in one step.

The fluorine-containing organic acid used is not particularly limited as long as it is an organic acid containing at least one fluorine atom in the molecule. As the fluorinated organic acid, for example,
Formula: Fluorine-containing carboxylic acid represented by R6COOH, Formula:
Fluorinated sulfonic acid represented by R6SO ₃ H, wherein: R6
Examples thereof include fluorine-containing sulfinic acid represented by SO ₂ H and phenols having a fluorine atom as a substituent on the benzene ring.

Here, R6 represents a fluoroalkyl group having 1 to 20 carbon atoms or a phenyl group substituted with a fluorine atom. Specific examples of the fluoroalkyl group having 1 to 20 carbon atoms include fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, heptafluoropropyl group, nona Fluorobutyl group, perfluoropentyl group,
Examples thereof include a perfluorohexyl group, a perfluoroheptyl group, a perfluorooctyl group, a perfluorononyl group, a perfluorodecyl group, a perfluoroundecyl group, and a perfluorododecyl group.

Specific examples of the phenyl group substituted with a fluorine atom include 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group and 2,6-difluoro group. Phenyl group,
Examples include 2,4,6-trifluorophenyl group and pentafluorophenyl group.

Specific examples of the fluorine-containing carboxylic acid include fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, 2,
Fluorine-containing aliphatic carboxylic acids such as 2,2-trifluoropropionic acid, pentafluoropropionic acid, heptafluorobutyric acid, heptafluoroisobutyric acid, nonafluorovaleric acid; 2-fluorobenzoic acid, 4-fluorobenzoic acid,
Fluorine-containing aromatic carboxylic acids such as 4-trifluoromethylbenzoic acid, 2,6-difluorobenzoic acid, 4-methyl-2-fluorobenzoic acid and pentafluorobenzoic acid;

Specific examples of the fluorine-containing sulfonic acid include fluoromethyl sulfonic acid, trifluoromethyl sulfonic acid, pentafluoroethyl sulfonic acid, 4-fluorobenzene sulfonic acid and the like. Specific examples of the fluorine-containing sulfinic acid include fluoromethylsulfinic acid and trifluoromethylsulfinic acid. Further, specific examples of phenols having a fluorine atom as a substituent on the benzene ring include 2-fluorophenol,
2,4-difluorophenol, pentafluorophenol, etc. are mentioned.

Among these, it is preferable to use a fluorinated carboxylic acid or a fluorinated sulfonic acid because the desired product can be obtained in a higher yield and the desired product can be easily isolated. The use of fluoroaliphatic carboxylic acids is more preferred, and the use of trifluoroacetic acid is especially preferred.

The amount of the fluorinated organic acid used is usually 0.0 with respect to 1 part by weight of the 1,3-dihydroxybenzene compound.
01-1,000 parts by weight, preferably 0.01-100
Parts by weight.

(D) Hydrogenation reaction In the present invention, a 1,3-dihydroxybenzene compound is hydrogenated to obtain a 1,3-cyclohexanedione compound (hereinafter, this reaction is referred to as "hydrogenation reaction"). .).

The hydrogenation reaction can be carried out without solvent or in a diluent. When a liquid fluorine-containing organic acid is used, it is preferable to carry out the hydrogenation reaction in the absence of a solvent, namely, the fluorine-containing organic acid, and more preferably to carry out the hydrogenation reaction in a liquid fluorine-containing carboxylic acid, It is particularly preferred to carry out the hydrogenation reaction in trifluoroacetic acid.

The diluent is not particularly limited as long as it is stable under the hydrogenation reaction conditions. Examples of the diluent to be used include water; alcohols such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, and tert-butyl alcohol; diethyl ether, tetrahydrofuran. , 1,
Ethers such as 3-dimethoxyethane and dioxane;
Aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane and n-octane; aromatic hydrocarbons such as benzene, toluene and xylene; cycloaliphatic such as cyclopentane, cyclohexane and 2-methylcyclohexane Hydrocarbons; amides such as N-methylpyrrolidone, dimethylformamide, dimethylacetamide; ureas such as dimethylimidazolidinone; sulfolane; and a mixed solvent composed of two or more of these.

The amount of the diluent used is not particularly limited,
The amount is usually 0.01 to 1,000 parts by weight, preferably 0.1 to 100 parts by weight, based on 1 part by weight of the 1,3-dihydroxybenzene compound.

In the hydrogenation reaction, predetermined amounts of the 1,3-dihydroxybenzene compound, the fluorine-containing organic acid and the hydrogenation catalyst are put in a closed reactor, and the inside of the reactor is replaced with hydrogen gas having a predetermined pressure. It is performed by stirring at a predetermined temperature.

The method for carrying out the hydrogenation reaction is not particularly limited, and either a batch system or a continuous system can be adopted.
Since the reactor used for the hydrogenation reaction uses a corrosive fluorine-containing organic acid, at least the inner wall is preferably made of a material having corrosion resistance to the acid. The size of the reactor can be appropriately selected according to the reaction scale.

As the hydrogen gas to be used, a pure one can be used, but a mixed gas obtained by diluting hydrogen gas with an inert gas such as nitrogen gas, argon gas or helium gas can also be used.

The pressure of hydrogen gas or mixed gas is usually 0.01 MPa to 10 MPa, preferably 0.1 MPa.
~ 1 MPa. The hydrogenation reaction temperature is usually from -10 ° C.
+ 250 ° C, preferably 0 ° C to + 100 ° C, more preferably + 10 ° C to + 80 ° C. The hydrogenation reaction time is usually 0.5 hours to 50 hours.

After completion of the hydrogenation reaction, if necessary, the hydrogenation catalyst is filtered off from the reaction solution, and the obtained filtrate is treated by a usual post-treatment operation such as distillation method, column chromatography, recrystallization method and the like. The target 1,3-cyclohexanedione compound can be obtained by known separation / purification means.

As described above, the 1,3-cyclohexanedione compound is obtained by selectively hydrogenating the carbon-carbon double bond at the 5- and 6-positions of the benzene ring of the 1,3-dihydroxybenzene compound.

Examples of the 1,3-cyclohexanedione compound include compounds represented by the above formula (2). Although the 1,3-cyclohexanedione compound represented by the formula (2) is a keto type, an enol type tautomer may exist. Both tautomers are included in the invention.

Specific examples of the 1,3-cyclohexanedione compound represented by the formula (2) include 1,3-cyclohexanedione; 2-methylcyclohexane-1,3-dione and 2-methoxycyclohexane-1,3. -Zeon, 2
-Trifluoromethylcyclohexane-1,3-dione, 2-methoxycarbonylcyclohexane-1,3-
Dione, 2-carboxycyclohexane-1,3-dione, 2-carboxymethylcyclohexane-1,3-dione, 2-ethoxycarbonylmethylcyclohexane-
2-substituted-1,3-cyclohexanedione compounds such as 1,3-dione;

4-methylcyclohexane-1,3-dione, 4-methoxycyclohexane-1,3-dione, 4
-Trifluoromethylcyclohexane-1,3-dione, 4-methoxycarbonylcyclohexane-1,3-
Dione, 4-carboxycyclohexane-1,3-dione, 4-carboxymethylcyclohexane-1,3-dione, 4-ethoxycarbonylmethylcyclohexane-
4-substituted-1,3-cyclohexanedione compounds such as 1,3-dione;

5-methylcyclohexane-1,3-dione, 5-methoxycyclohexane-1,3-dione, 5
-Trifluoromethylcyclohexane-1,3-dione, 5-methoxycarbonylcyclohexane-1,3-
Dione, 5-carboxycyclohexane-1,3-dione, 5-carboxymethylcyclohexane-1,3-dione, 5-ethoxycarbonylmethylcyclohexane-
5-substituted-1,3-cyclohexanedione compounds such as 1,3-dione;

4,5-Dimethylcyclohexane-1,3
-Dione, 4-methoxy-5-methylcyclohexane-
4,5-disubstituted-1,3-cyclohexanedione compounds such as 1,3-dione and 4-trifluoromethyl-5-methylcyclohexane-1,3-dione;

2,4-dimethylcyclohexane-1,3
-Dione, 2-methoxy-4-methylcyclohexane-
2,4-disubstituted-1,3-cyclohexanedione compounds such as 1,3-dione and 2-trifluoromethyl-4-methylcyclohexane-1,3-dione;

2,5-dimethylcyclohexane-1,3
-Dione, 2-methoxy-5-methylcyclohexane-
2,5-disubstituted-1,3-cyclohexanedione compounds such as 1,3-dione and 2-trifluoromethyl-5-methylcyclohexane-1,3-dione;

4,5,6-Trimethylcyclohexane-
4,5,6-tri-substituted-1,3-diones such as 1,3-
Cyclohexanedione compound; and the like. Among these, mono-substituted-1,3-cyclohexanedione compounds are preferable, and cyclohexane-1,3-dione is particularly preferable.

1,3-obtained by the production method of the present invention
The cyclohexanedione compound is useful as an intermediate for the production of various medicines and agricultural chemicals.

[0059]

EXAMPLES Next, the present invention will be further described with reference to examples. The present invention is not limited to the following examples, and the types of 1,3-dihydroxybenzene compounds, fluorine-containing organic acids and the amounts thereof used can be freely changed without departing from the gist of the present invention. it can. The parts used in the following examples and comparative examples are based on weight unless otherwise specified.

Example 1 Cyclohexane-1,3-dio
The glass stirrer and 1,500 parts of trifluoroacetic acid were placed in a glass two-necked flask. There resorcinol 1
01 parts was added and dissolved, and 10 parts of a 5 wt% platinum-supported alumina catalyst (manufactured by Aldrich) was added. After replacing the inside of the flask with nitrogen gas and then with hydrogen gas, the reaction mixture was vigorously stirred at room temperature for 12 hours under a hydrogen atmosphere at atmospheric pressure. After completion of the reaction, the reaction solution was filtered through Celite to remove the catalyst, and the solvent (trifluoroacetic acid) was distilled off from the filtrate under reduced pressure to obtain 91.1 parts of a pale yellow solid (product) (yield = 88% )Obtained. When this product was analyzed by silica gel thin layer chromatography, the product was a single product, and its Rf value was in agreement with that of the standard product (1,3-cyclohexanedione). The Rf value is a value obtained by dividing the distance from the development origin where the sample (product) was first applied to the center of the color development spot of the sample by the distance from the development origin to the development tip of the development solvent. Moreover, it was confirmed that this product was 1,3-cyclohexanedione by measuring ¹ H-NMR and mass spectrum of the obtained product.

[0061]

According to the present invention, a 1,3-cyclohexanedione compound can be produced in a high yield in one step under mild reaction conditions that do not require high temperature and high pressure.

Claims (3)

[Claims] 1. A 1,3-dihydroxybenzene compound,
A method for producing a 1,3-cyclohexanedione compound, which comprises hydrogenating in the presence of (a) a hydrogenation catalyst and (b) a fluorine-containing organic acid. 2. The 1,3-dihydroxybenzene compound is represented by the formula (1): [In formula, R1, R2, R3, and R4 are respectively independently a hydrogen atom, a C1-C6 alkyl group, and a C3-C3.
6 cycloalkyl groups, C 1-6 alkoxy groups,
Haloalkyl group having 1 to 6 carbon atoms, which may have a substituent phenyl group or a group represented by the formula _:-( CH ₂₎ n COOR5,
(In the formula, n is 0 or an integer of 1 to 6, and R5 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.)]
Wherein the 1,3-cyclohexanedione compound is a compound represented by the formula (2): The method according to claim 1, which is a compound represented by the formula (wherein R 1, R 2, R 3 and R 4 have the same meanings as described above) or an enol tautomer thereof. 3. The method according to claim 1, wherein trifluoroacetic acid is used as the fluorine-containing organic acid.