JPS61130283A - Production of flavonecarboxylic acid ester - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as a medicinal drug, in high conversion, yield and selectivity, by reacting a flavonecarboxylic acid ester with an alcohol using an acetylacetone complex salt as a catalyst. CONSTITUTION:The fravonecarboxylic acid ester of formula II is produced by reacting a flavonecarboxylic acid ester of formula I (R<1> is alkyl, aralkyl or aryl; R<2> and R<3> are H, alkyl or halogen; R<4> is H, alkyl or aryl) with an alcohol of formula R<5>OH (R<5> is alkyl, aralkyl, monohydroxyalkyl or aminoalkyl different from R<1>) using an acetylacetone complex salt (e.g. acetylacetone zinc salt) as a catalyst. The amount of the catalyst is about 0.001-1mol, preferably 0.005-0.5mol per 1mol of the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing flavonecarboxylic acid esters, and more particularly to a method for producing flavonecarboxylic acid esters by transesterification using an acetylacetone complex salt as a catalyst.

(Prior Art) Basic esters of 3-methylflavone-8-carboxylic acid useful as pharmaceuticals, such as β-piperidinoethyl ester, β-morpholinoethyl, β-diethylaminoethyl ester, β-di-n-propylamino Ethyl ester or β-di-isopropylaminoethyl ester is conventionally produced by esterification of 3-methylflavone-8-carboxylic acid with an amino alcohol or by esterification of lower alkyl ester of 3-methylflavone-8-carboxylic acid. It is already known that they can be produced by conversion reactions.

For example, Japanese Patent Publication No. 51-4983 describes a method for producing β-piperidinoethyl ester of 3-methylflavone-8-carboxylic acid, in which the ethyl ester of the former is prepared using sodium piperidinoethanolate as a catalyst. A method of transesterification with piperidinoethanol is disclosed. However, according to the method using the above catalyst, both the conversion rate of the raw ester and the yield of piperidinoethyl ester are low.

(Problems to be Solved by the Invention) The present invention aims to provide a method for producing flavonecarboxylic acid esters such as 3-methylflavone-8-carboxylic acid ester with high raw material conversion rate and high yield. purpose.

(Structure of the Invention) The present invention is based on the general formula (I) (wherein R1 represents an alkyl group, an aralkyl group, or an aryl group, R2 and R3 each independently represent hydrogen, an alkyl group, or a halogen, and R4 represents hydrogen , an alkyl group or an aryl group), and flavone carboxylic acid esters represented by the general formula (n) R'OH (wherein R5 is an alkyl group, an aralkyl group, a monohydroxyalkyl group different from the above R1, or An aminoalkyl group) is reacted with an alcohol represented by the general formula (wherein R2, R3, R4 and R5 are the same as above) to obtain flavonecarboxylic acid esters represented by the general formula (where R2, R3, R4 and R5 are the same as above) The manufacturing method is characterized by using an acetylacetone complex salt as a catalyst.

The raw material flavonecarboxylic acid esters used in the present invention are represented by the above general formula, where R1 is methyl,
Alkyl groups such as ethyl, n-propyl, isopropyl, n-butyl and isobutyl, particularly preferably alkyl groups having 5 or less carbon atoms, aralkyl groups such as benzyl and phenethyl, or aryl groups such as phenyl, tolyl and xylyl. .

R2 and R3 are each independently hydrogen, methyl, ethyl,
an alkyl group such as n-propyl, isopropyl, n-butyl, isobutyl, particularly preferably an alkyl group having 5 or less carbon atoms, or a halogen such as chlorine, bromine, d-fluorine, or fluorine, and R2 is at the 5-position , located at the 6- or 7-position,
Further, R4 is an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, particularly preferably an alkyl group having 5 or less carbon atoms, or an aryl group such as phenyl, tolyl or xylyl.

Specific examples of such raw material flavonecarboxylic acid esters include methyl ester, ethyl ester, etc. of 3-methylflavone-8-carboxylic acid, and methyl ester, ethyl ester, etc. of 3-ethylflavone-8-carboxylic acid. can be mentioned.

Further, the alcohol used in the present invention is represented by the general formula (I[), where R5 is the general formula (I[)].
), an alkyl group or an aralkyl group different from R+ in
It is a monohydroxyalkyl group or an aminoalkyl group. Here, as the alkyl group, methyl, ethyl, n-
Examples include alkyl groups such as propyl, isopropyl, n,-butyl, and isobutyl, aralkyl groups such as benzyl and phenethyl, and monohydroxyalkyl groups such as β-hydroxyethyl and T-hydroxy-n-propyl.Aminoalkyl groups include is β-piperidinoethyl, β-morpholinoethyl, β-dimethylaminoethyl, β-diethylaminoethyl, β-di-n-propylaminoethyl,
Examples include β-diisopropylaminoethyl, dimethylaminopropyl, diethylaminopropyl, and the like.

The catalyst used in the present invention is an acetylacetone complex salt, and is represented by the general formula (IV) M(CIbCOCHCOCHz) - (wherein M represents a metal atom and n represents an integer of 1 to 4). Specific examples include zinc acetylacetonate,
Examples include iron acetylacetonate, cobalt acetylacetone, manganese acetylacetone, copper acetylacetone, and aluminum acetylacetone, among which zinc acetylacetone and iron iron acetylacetone are preferably used.

The acetylacetone complex salt as a catalyst is usually used in an amount of about 0,00 to about 1 mol per 1 mol of the raw material flavonecarboxylic acid ester represented by the general formula (I), particularly preferably about 0 , 0-05 to about 0.5
Used in molar range.

The transesterification reaction of flavonecarboxylic acid esters according to the present invention is usually carried out in an inert solvent, and examples of the inert solvent include dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, Sulfolane, benzene, toluene, xylene, cumene, chlorobenzene, dichlorobenzene, etc. are preferably used.

These solvents are usually used in a proportion of about 0.1 to about 100 parts by weight, preferably about 17X+ to about 10 parts by weight, per 1 part by weight of the starting flavonecarboxylic acid ester represented by the general formula (I). It is used in the reaction, and is added as necessary during the reaction.

In the present invention, the ratio of the raw material flavonecarboxylic acid esters represented by general formula (I) and the alcohols represented by general formula (II) is not particularly limited, but
It is preferable to use about 0.9 to about 10 moles, preferably about 1 to about 2 moles, of the above-mentioned alcohols per mole of the raw material flavonecarboxylic acid ester because the reaction efficiency is high. Therefore, the raw materials may be added in the above ratio during the reaction, or a method may be adopted in which the raw materials are added at any time so as to maintain the above range.

In the present invention, the transesterification reaction is usually about 50
The reaction is carried out at a reaction temperature of .degree. C. to about 200.degree. C. for about 1 to about 24 hours, preferably about 3 to about 12 hours. Furthermore, as the reaction progresses, it is desirable to remove alcohols or phenols produced by transesterification from the reaction system as needed. Therefore, the reaction is preferably carried out under heating to reflux to distill off the alcohols or phenols. Alternatively, an inert gas such as nitrogen or argon may be blown into the reaction system to distill off the alcohols or phenols.

Furthermore, in the present invention, from an industrial standpoint, it is desirable to carry out the reaction until the transesterification is substantially completed. Here, the term "the transesterification reaction is substantially completed" means that even if the transesterification reaction is continued for an additional 2 hours,
This refers to a state in which no change in the yield of ester, which is the target compound represented by the general formula (I[), is observed within the analytical error range.

In the present invention, the reaction can be carried out either batchwise or continuously. Furthermore, the reaction does not necessarily require any special equipment; for example, the reaction can be carried out in a normal reaction vessel equipped with a stirring device, a heating device, an addition device, a distillation device, etc.

The flavonecarboxylic acid esters as the target compound represented by the general formula (III) obtained as described above can be prepared by conventional methods known in the art, such as distillation,
It can be separated and purified by methods such as recrystallization.

(Effects of the Invention) According to the present invention, by using an acetylacetone complex salt as a catalyst in the transesterification reaction of flavonecarboxylic acid esters, β-piperidinoethyl ester of 3-methylflavone-8-carboxylic acid, etc. Flavonecarboxylic acid esters can be produced with high raw material conversion, high yield, and high selectivity.

(Example) Next, the present invention will be specifically explained using examples.

Example 1 14.72 g (0.05 mol) of methyl 3-methylflavone-8-carboxylate and 7.75 g of β-piperidinoethanol were placed in a 200 ml three-necked flask equipped with a stirrer, a condenser, and a thermometer. (0.06 mol), 0.13 g (0.0005 mol) of zinc acetylacetone, and 50 ml of toluene were charged, and the reaction was carried out for 15 hours while refluxing the toluene by passing hot water at 80° C. into a condenser. Toluene and an aqueous sodium hydroxide solution were added to the reaction mixture and stirred, followed by oil and water separation, and the oil layer was washed with water and dried, concentrated, and 19.25 g of β-piperidinoethyl 3-methylflavone-8-carboxylate (gas chromatography (purity 99.0%) was obtained.

On the other hand, the alkaline aqueous layer was made acidic with hydrochloric acid, extracted with ethyl acetate, washed with water, dried, and concentrated to obtain 0.28 g of 3-methylflavone-8-carboxylic acid. Therefore, in this reaction, the conversion rate of methyl ester was 99.9
%, the yield of β-piperidinoethyl ester is 97.4%
The selectivity was 97.5%, and the yield of carboxylic acid was 2.0%.

Example 2 The reaction was carried out in the same manner as in Example 1, except that the acetylacetone complex salt shown in Table 1 was used instead of zinc acetylacetone as a catalyst. The results are shown in Table 1.

Example 3 Example 1 except that the alcohol shown in Table 2 was used instead of β-piperidinoethanol in Example 1.
The reaction was carried out in the same manner as above, and the results shown in Table 2 were obtained.

Table 1 (Note) acac indicates acetylacetone.

Example 4 The reaction was carried out in the same manner as in Example 1, except that the esters shown in Table 3 were used instead of methyl 3-methylflavone-8-carboxylate as the raw material ester. The results shown in the table were obtained.

Example 5 The reaction was carried out in the same manner as in Example 1, except that the solvent shown in Table 4 was used instead of toluene as the solvent, and the results shown in Table 4 were obtained.

Example 6 5.89 g (0.02 mol) of methyl 3-methylflavone-8-carboxylate was placed in a 100 ml four-bottle flask equipped with a stirrer, condenser, thermometer and gas injection tube.
, 3.10 g (0,024 mol) of β-piperidinoethanol, 0.26 g (0,001 mol) of zinc acetylacetonate, and 40 ml of dimethylformamide were heated at 100°C for 12 hours while blowing dry nitrogen gas at a rate of Il/min. After the time reaction, post-treatment was performed in the same manner as in the example.

The conversion rate of methyl ester is 99.8%, the yield of β-piperidinoethyl ester is 98.6%, and the selectivity is 98.8.
%Met.

Claims (1)

[Claims] 1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents an alkyl group, an aralkyl group, or an aryl group, and R^2 and R^3 are hydrogen,
It represents an alkyl group or a halogen, and R^4 represents hydrogen, an alkyl group, or an aryl group. ) and the general formula (II) R^5OH (wherein R^5 represents an alkyl group, an aralkyl group, a monohydroxyalkyl group, or an aminoalkyl group different from the above R^1). ) is reacted with alcohols represented by the general formula (I
II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^2, R^3, R^4 and R^5 are the same as above.) To produce flavonecarboxylic acid esters represented by A method for producing flavonecarboxylic acid esters, characterized in that the method uses an acetylacetone complex salt as a catalyst.