JPH11116527A - Production of 2-substituted-1,3-indanedione derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing, in high yield, the subject compound useful as an intermediate for medicines and agrochemicals by adding water to a reaction mixture containing a specific indanedione derivative to separate it into the aqueous phase and organic solvent phase, and separating the water phase after keeping it at a specific pH level. SOLUTION: This compound is obtained by adding water to a reaction mixture containing a 2-substituted-1,3-indanedione derivative shown by formula III to transfer the derivative into the aqueous phase, separating the mixture into the aqueous phase and organic solvent phase, and separating the aqueous phase after keeping it at pH 4 to 8, wherein the compound shown by formula III is obtained by reacting an ester shown by formula I (R1 is a 1-10C alkyl, 2-10 alkenyl or the like; and R2 is a 1-4C alkyl) with a phthalic ester derivative shown by formula II (R3 is a 1-4 alkyl; R4 to R7 are each H, a 1-10C alkyl or the like) in the presence of a base (e.g. sodium hydride or sodium methoxide), preferably at 100 to 150 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a disubstituted-1,3-indandione derivative useful as an intermediate for medicines and agricultural chemicals.

[0002]

2. Description of the Related Art A method for producing a 2-substituted-1,3-indandione derivative useful as an intermediate for pharmaceuticals and agrochemicals includes an ester represented by the general formula (1): A production method in which a phthalate derivative represented by the general formula (2) is reacted in the presence of a base (JP-A-9-20715) is useful. However, when the present inventors studied the above-mentioned production method, the obtained reaction mixture contained the phthalate derivative represented by the general formula (2) and the ester represented by the general formula (1). Is a by-product of the reaction of two or more, or general formula (1)
And a by-product obtained by reacting the esters represented by the formula (2).
Since it has the same properties as the 1,3-indandione derivative, the purification of the product, 2-substituted-1,3-indandione represented by the general formula (3), becomes very difficult. I was Further, 2-substituted-1, represented by the general formula (3),
It is difficult to improve the purity by crystallization of the 3-indandione derivative, and the 2-substituted-1,1 represented by the general formula (3) has high purity.
It was very difficult to obtain a 3-indandione derivative.

[0003]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a disubstituted-1,3-indandione derivative represented by the general formula (3) is reacted with a derivative. The present inventors have found that an impurity having properties similar to those of a generated product has a different distribution ratio between an organic solvent phase and an aqueous phase in a specific pH range, thereby completing the present invention. That is, the gist of the present invention is represented by the following general formula (1)

[0004]

Embedded image R1CH ₂ COOR2 (1)

(Wherein R1 and R2 have the same definitions as the above-mentioned definitions), and an ester represented by the following general formula (2)

[0006]

Embedded image

(Wherein R3, R4, R5, R6 and R7 have the same definition as above) with a phthalate derivative represented by the following general formula: Equation (3)

[0008]

Embedded image

(Wherein R1, R4, R5, R6 and R7 have the same definition as the above). A reaction mixture containing a disubstituted-1,3-indandione derivative represented by the following formula: Water is added to the mixture to extract the disubstituted-1,3-indandione derivative represented by the above general formula (3) into the aqueous phase, and to separate the aqueous phase from the organic solvent phase. A separation step, the aqueous phase obtained in the first separation step is adjusted to pH 4 to 8, and a step of fractionating the 2-substituted-1,3-indandione derivative represented by the general formula (3) is carried out. A method for producing a disubstituted-1,3-indandione derivative represented by the above general formula (3), wherein the disubstituted-1,3-indandione derivative represented by 3) is fractionated. .

[0010]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred specific embodiments of the present invention will be described below. In the above general formula, carbon number 1
Examples of the alkyl group of 10 to 10 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a pentyl group, a neopentyl group, a hexyl group, a 2-methyl-hexyl group, a heptyl group, an octyl group, and a decyl group. 2 carbon atoms
Examples of the alkenyl group of 10 include an ethenyl group, a 1-propenyl group, a 1-hexenyl group, a 2-ethyl-2-butenyl group, a 2-octenyl group, a (4-ethenyl) -5-hexenyl group, a 2-decenyl group, Examples of the alkynyl group having 2 to 10 carbon atoms include an ethynyl group, 1-propynyl group, 1-butynyl group, 1-pentynyl group, 1-hexynyl group, 2-ethyl-2-butynyl group, 2-octynyl group, (4 -Ethynyl) -5-hexynyl group, 2-decynyl group and the like. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and the like. Examples of the alkoxyl group having 1 to 10 carbon atoms include a methoxy group and an ethoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the present invention, R1 has 1 carbon atom.
An alkyl group having 10 to 10 is preferable, and an alkyl group having 1 to 4 carbon atoms is more preferable. R2 has 1 carbon atom
And C4 to C4 alkyl groups, more preferably C1 to C2 alkyl groups. R4 to R7 are preferably a hydrogen atom, an alkyl group having 1 to 10 carbon atoms and a halogen atom, more preferably a hydrogen atom, an alkyl group having 1 to 4 carbon atoms and a halogen atom, and particularly preferably a hydrogen atom. . Generally, in the present invention, the following general formula (1)

[0012]

Embedded image R1CH ₂ COOR2 (1)

(In the above formula, R1 and R2 have the same definition as the above.) And an ester represented by the following general formula (2)

[0014]

Embedded image

(Wherein R3, R4, R5, R6 and R7 have the same definition as above) and a phthalate derivative represented by the following formula: The reaction is carried out in a base under heating, and after completion of the reaction, the reaction is stopped by adding water, and after washing with an organic solvent, the aqueous phase is acidified and separated as crystals, or the aqueous phase is acidified and mixed with an organic solvent. By contacting, separating and concentrating the organic solvent, the following general formula (3)

[0016]

Embedded image

(Wherein R1, R4, R5, R6 and R7 have the same definition as described above) to produce a 2-substituted-1,3-indandione derivative represented by the formula:
Examples of the base used in the present invention include, for example, Periodic Table I
Or a hydride of a Group II metal or Periodic Table I or
And alkoxides of Group II metals. As hydrides of Group I or II metals of the periodic table, sodium hydride,
Potassium hydride, calcium hydride, and the like. Examples of the alkoxide of Group I or Group II metal include sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, and magnesium ethoxide. And the like. Of these, hydrides and alkoxides of sodium and potassium are particularly preferred.
When an alkoxide of a metal of Group I or Group II of the periodic table is used as the base, it is preferable to perform an operation of removing the alcohol from the reaction system in view of the reaction rate and the reaction yield.

In the present invention, the amount of the ester represented by the above formula (1) is not particularly limited, but from the viewpoint of the reaction yield, the phthalate ester represented by the above formula (2) is used. It is preferable to use 10 to 300 mol% based on the derivative. The amount of the base used in the present invention is 50 to 50 with respect to the ester represented by the above formula (1).
0 mol%, preferably in the range of 80 to 300 mol%.

The reaction of the present invention is carried out without a solvent or in a state diluted with a solvent. The solvent used for dilution is not particularly limited as long as it is a solvent inert to the reaction.Hexane, octane, benzene, toluene, hydrocarbons such as xylene, halogenated hydrocarbon solvents such as chlorobenzene, diethyl ether, Examples include ether solvents such as tetrahydrofuran, dioxane, dibutyl ether, dimethoxyethane, and diethoxyethane. Further, when using an alkoxide of a metal of Group I or Group II of the periodic table as a base and removing the alcohol to the outside of the reaction system, a solvent having a boiling point of 100 ° C to 150 ° C may be used. From the viewpoints of the removal of, the reaction rate and the reaction yield. The amount of the solvent used is not particularly limited, but is preferably 0 to 100 times (weight), more preferably 2 to 100 times the amount of the phthalate derivative.
It is carried out in the range of 30 times the amount.

The reaction temperature of the present invention is usually from 0 to 300 ° C.
Preferably 50 to 200 ° C., more preferably 100 to 200 ° C.
It is performed in a temperature range of 150 ° C. In the present invention, water is added to the reaction mixture of the compound generated in the above reaction,
The disubstituted-1,3-indandione derivative represented by the above formula (3) is extracted into an aqueous phase under a condition of not less than 8, preferably not less than pH 10, and separated by liquid separation. The amount of water to be added is not particularly limited.
The range is 100 times by weight, preferably 2 to 30 times by weight. Further, an additive such as a base or an inorganic salt may be added to the water to be added for the purpose of improving the distribution ratio, improving the liquid separation property, and the like. The temperature at the time of performing the extraction and liquid separation operations is usually in the range of 0 to 100 ° C, preferably 10 to 70 ° C, and more preferably 10 to 50 ° C.

The organic (reaction) solvent phase separated by the above-mentioned extraction contains carbonate by-produced in the reaction, and when an aqueous alkali solution is added thereto and mixed by heating, carbonates produced as a by-product in the reaction are added. Can be decomposed and extracted and removed to the aqueous phase, so that the solvent can be recycled and industrially preferable.

The alkali is not particularly limited as long as it is water-soluble, and examples thereof include sodium hydroxide, potassium hydroxide, calcium hydroxide, and ammonia. The amount of the alkali used is not particularly limited as long as it is at least 2 equivalents to the carbonates contained in the mixture. The above by-product decomposition reaction is usually carried out at a temperature in the range of 30 to 150 ° C, preferably 40 to 100 ° C.

On the other hand, the pH of the aqueous phase obtained by the above extraction is adjusted to 4 to 8 by adding acid or the like, and the 2-substituted
The 1,3-indandione derivative is collected. As described in JP-A-9-20715, the pH at the time of fractionation
Is about 3, but the pH at the time of fractionation is such that the purity of the fractionated 2-substituted-1,3-indandione derivative decreases on the strongly acidic side, and the yield of fractionation decreases on the alkaline side, There is an optimal pH range specific to the particular disubstituted 1,3-indandione derivative of interest. For example, in the case of 2-ethyl-1,3-indandione, the pH is particularly in the range of 5 to 7. Examples of the acid used include inorganic acids such as hydrochloric acid and sulfuric acid.

In the present invention, when the pH of the aqueous phase containing the disubstituted-1,3-indandione derivative represented by the above formula (3) is adjusted to an optimum range, the contained disubstituted-1,3-indandione derivative is included
The 3-indandione derivative crystallizes and can be collected by filtration. The fractionation is performed in a temperature range of 0 to 100 ° C, preferably in a temperature range of 5 to 50 ° C. In the present invention, 2-substituted-1, represented by the above formula (3),
When adjusting the pH of the aqueous phase containing the 3-indandione derivative to an optimal range, if an organic solvent is allowed to coexist in the system,
The disubstituted-1,3-indandione derivative can be extracted and fractionated in an organic phase. The solvent for extracting the 2-substituted-1,3-indandione derivative is not particularly limited as long as it is a solvent that is inert to the substrate, and examples thereof include the above-mentioned reaction solvents.

[0025]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples unless it exceeds the gist thereof.

Example 1 500 ml of toluene, 90%
Sodium ethoxide 50.0 g (0.66 mol),
A flask was charged with 100 g (0.45 mol) of diethyl phthalate and 47.4 g (0.41 mol) of ethyl butyrate, and reacted for 18 hours by heating and refluxing while distilling off toluene and by-produced ethanol using a rectification column. I let it.
On the way, 10.5 g of ethyl butyrate (0.09 m
ol) and 30 g of toluene, 13 hours later, ethyl butyrate 1
0.5 g (0.09 mol) and 10 g of toluene were added. The conversion of the reaction is 92% with respect to diethyl phthalate,
The reaction yield was 83% with respect to diethyl phthalate, and the selectivity was 90%. After cooling the reaction solution, 500 ml of water was added for dissolution, and after separation, the aqueous phase was washed with 200 ml of toluene.
Concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 6, and acid precipitation was performed, followed by filtration to obtain 2-ethyl-1,3-indandione. The purity of the obtained crystals was 96%, and the takeout yield was 95%.

15% was added to the toluene phase obtained by the separation.
500 ml of an aqueous sodium hydroxide solution was added, and the mixture was treated at 70 ° C. for 1 hour. Further, after cooling, the toluene phase obtained by liquid separation was distilled to recover toluene. As a result, impurities such as diethyl carbonate by-produced in the reaction were below the detection limit in the recovered toluene, and could be reused in the reaction. In addition, the aqueous alkali solution after the separation contained ethanol and the like generated by decomposition of diethyl carbonate.

<Example 2> After cooling the reaction solution obtained by the same reaction procedure as in Example 1, 500 ml of water was added to dissolve and separate the solution, and the aqueous phase was washed with 200 ml of toluene. Next, 200 ml of toluene was added to the aqueous phase, and the pH was adjusted with concentrated hydrochloric acid.
Was adjusted to 6 and 2-ethyl-1,3-indandione was extracted into the toluene phase. The concentration of 2-ethyl-1,3-indandione in the components other than toluene in the toluene phase was 96%, and the extraction yield was 97%.

<Comparative Example> After cooling the reaction solution obtained by the same reaction procedure as in Example 1, 500 ml of water was added to dissolve and separate the solution, and the aqueous phase was washed with 200 ml of toluene. Next, 200 ml of toluene was added to the aqueous phase, the pH was adjusted to 3 with concentrated hydrochloric acid, and 2-ethyl-1,3-indandione was extracted into the toluene phase. After concentration, crystallization was performed in a methanol / water system to obtain 2-ethyl-1,3-indandione. 2-ethyl-1,3-indandione purity is 90
%, And the removal yield was 95%.

[0030]

According to the present invention, a 2-substituted-1,3-indandione derivative useful as an intermediate of medicines and agricultural chemicals can be obtained with high purity, and its industrial value is high.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 49/697 C07C 49/697 49/755 49/755

Claims (4)

[Claims] 1. A compound represented by the following general formula (1): R 1 CH ₂ COOR ₂ (1) (wherein R 1 is an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or 2 to 2 carbon atoms) And R 2 represents an alkyl group having 1 to 4 carbon atoms), and an ester represented by the following general formula (2): (In the above formula, R3 represents an alkyl group having 1 to 4 carbon atoms;
R4, R5, R6 and R7 are each independently a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, and an alkoxyl group having 1 to 10 carbon atoms. Represents a group or a halogen atom. The following general formula (3) obtained by reacting a phthalate derivative represented by the formula (1) in the presence of a base: (In the above formula, R1, R4, R5, R6 and R7 are as defined in general formulas (1) and (2).)
The reaction mixture containing the substituted-1,3-indandione derivative is extracted with water added to the mixture to extract the disubstituted-1,3-indandione derivative represented by the general formula (3) into an aqueous phase. Then, a first separation step of separating the aqueous phase and the organic solvent phase, the aqueous phase obtained in the first separation step is adjusted to pH 4 to 8, and the 2-substituted 1,3-formula represented by the above general formula (3) is set. A step of fractionating the indandione derivative, wherein the disubstituted-1,3-indandione derivative represented by the above general formula (3) is fractionated, represented by the above general formula (3). A method for producing a disubstituted-1,3-indandione derivative. 2. The production of a disubstituted-1,3-indandione derivative according to claim 1, wherein the pH of the step of fractionating the disubstituted-1,3-indandione derivative is 5 to 7. Method. 3. A disubstituted compound represented by the above general formula (3)
The method for fractionating a 1,3-indandione derivative is extraction into an organic solvent, wherein the 2-substituted-1,3-indandione represented by the general formula (3) according to claim 1, is used. A method for producing a derivative. 4. A disubstituted compound represented by the above general formula (3)
2. The method for producing a disubstituted-1,3-indandione represented by the general formula (3) according to claim 1, wherein the method for fractionating the 1,3-indandione derivative is crystallization. .