JPS59212485A - Preparation of flavonecarboxylic acid ester - Google Patents

Abstract

PURPOSE:To prepare the titled compound in high yield, by the ester-exchange reaction of a flavonecarboxylic acid ester with an alcohol using an alkali metal carbonate as a catalyst. CONSTITUTION:The ester of formula II is prepared by reacting the flavone- carboxylic acid ester of formula I (R<1> is alkyl, aralkyl, etc.; R<2> and R<3> are H, alkyl or halogen; R<4> is H, alkyl or aryl) with the alcohol of formula R<5>OH (R<5> is alkyl, aralkyl, etc. different from R<1>). The reaction is caried out in the presence of usually about 0.001-1mol, based on 1mol of the flavonecarboxylic acid ester used as a raw material, of an alkali metal carbonate (e.g. potassium carbonate) as a catalyst, usually in the presence of an inert solvent (e.g. dimethyl formamide). The alcohol produced by the ester-exchange reaction is preferably removed from the reaction system according to the progress of the reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION 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 alkali metal carbonate as a catalyst.

Basic esters of 6-methyl-flavone-8-carboxylic acid, such as β-piperidino-ethyl, β-morpholino-
Ethyl, β-diethy/Vl aminodiethi β-di-n
-Propylamino-ethyl or β-diinopropylaminoethyl and the like are known as pharmaceuticals.

In addition, the production of the basic ester of ro-methylsoflavone-8-carboxylic acid includes an esterification reaction of 6-methyl-soflavone-8-carboxylic acid or its lower alkyl ester with aminoalco-)v, etc. Alternatively, it is also known to utilize an ester conversion reaction.

For example, Tokuko Sho 51. In Example 9 of Publication No. 4983,
As a method for producing β-piperidino-ethyl ester of 6-methyl-flavone-8-carboxylic acid, a method is disclosed in which ethyl ester is transesterified with piperidino-ethanol, and sodium metal is dissolved in piperidino-ethanol as a catalyst. It is used in this manner. However, when sodium biperidino ethanolate is used as a catalyst, both the conversion rate of the raw material and the yield of piperidino-ethyl ester are low.

The present invention provides a method for producing esters of flavonecarboxylic acids such as 5-methyl-flavone-8-carboxylic acid with a high raw material conversion rate and high yield, and uses an alkali metal carbonate as a catalyst. It relates to a method for producing flavonecarboxylic acid esters using ester conversion G.

That is, the present invention is based on the general formula (1) (wherein R1 represents an alkyl group, ara, .regyl group, or aryl group, R2 and R6 each represent hydrogen, an alkyl group, or a halogen, and , an alkyl group or an IJ)Ly group), and the general formula DR50H (
It) (in the formula, R5 represents an argyl group, an aralkyl group, a monohydroxyalkyl group, or an aminoalkyl group different from the above R1) to form the general formula []1] (in the formula , R, R, R and R5 are the same as above), characterized in that an alkali metal carbonate is used as a catalyst. This invention relates to a method for producing varnishes.

The flavonecarboxylic acid esters represented by the general formula [1] used in the present invention include the general formula CI
') in n' Camethyl, ethyl, n-brohy”nol
/S is an argyl group such as isopropyl, 11-butyl, isobutyl, particularly preferably an argyl group having 5 or less carbon atoms, an aralkyl group such as hensyl, phenethyl, or an ary-71z group such as phenyl, tolyl, xylyl,
R and R6 are hydrogen, methyl, ethylV, n, respectively
- Alkyl groups such as propyl, isopropyl n-butyl, isobutyl, particularly preferably alkyl groups having 5 or less carbon atoms, bromine, iodine, fluorine, etc., R
2 is an alkyl group such as methyl, ethyl, n-propyl, isopropyl, 1-butyl, inobutyl,
Or it is a compound represented by an aryl group such as phenyl, tolyl, or xylyl. More specifically, the 4C compound may include methyl ester of 6-methyl-Flapone-8-carboxylic acid and methyl ester of esterboxylic acid.

Further, the alcohol represented by the general jKCV used in the present invention is a compound in which the alcohol represented by the general formula [I] is an alkylaralkyl aminoalkyl group different from R1 in the general formula [I]. alkyl group, methyl, ethyl, n-propyllopyl, n-butyl,
Examples include alkyl groups such as isobutyl, aralkyl groups such as benzyl and phenethyl, and monohydroxyalkyl groups such as β-hydroxy-ethyl and r-hydroxy-〇-propyl.Aminoalkyl groups include β-piperidino-ethyl, Examples include β-morpholino-ethyl, β-dimethylamino-ethyl, β-diethylamino-ethyl, β-di1]-propylamino-ethyl, β-diisobutylamino-ethyl, dimethylaminopropyl, diethylaminopropyl, etc. .

The catalyst used in the present invention is at least one compound selected from alkali metal carbonates, such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, thorium hydrogen carbonate, rubidium carbonate, and sesium carbonate. Among them, potassium carbonate and potassium hydrogen carbonate are preferred.

The alkali metal carbonate is usually used in an amount of about 0.00 + to about 1 mol, particularly preferably about 0.005 mol, per 1 mol of the raw material flavonecarboxylic acid ester represented by the general formula (1). The amount used is from about 0.5 mol to about 0.5 mol.

The reaction of the present invention is usually carried out in the presence of a solvent inert to the reaction. Specifically as a solvent ('', dimethylformamide, dimethylacetamide, diethylformamide,
Examples include 1-coumethylpyrrolidone, tetramethytv urea, dimethyl sulfoxide, 1-coumethyl pyrrolidone, acetonitrile, propionitrile, sulfolane, and the like.

These solvents are usually used in a proportion of about 0.1 to about 100 parts by weight, preferably about 1 to about 40 parts by weight, per 1 part by weight of the raw material flavone cuff levonic acid ester represented by the general formula (1). It is used in the reaction (additional addition is made as necessary at this time).

In the reaction of the present invention, the raw material flavone carboxylic acid ester represented by the general formula [I] and the alcohol represented by the general formula CIIJ are not used. The reaction efficiency is good when the amount is about 0.9 to about 10 moles, preferably about 1 to about 27 moles.

, 2, it is possible to adopt a method of adding the raw materials in the above-mentioned ratio, or a method of adding the raw materials at any time so that the ratio is within the above range.

The reaction of the present invention is generally carried out at a reaction temperature of about 50° to about 200°.
C for about 1 to about 24 hours, preferably about 5 to about 1
It will last about 2 hours.

As the reaction progresses, it is desirable to remove DE from the raw alcohol thread by Nisdell exchange from time to time, for example about 1%.

The reaction can be carried out while distilling off under a reduced pressure of 50 to about 50 mmHg, or an inert gas such as nitrogen or argon can be blown into the reaction system and the reaction can be carried out while distilling off. is desirable.

The reaction of the present invention (J1) From an industrial standpoint, it is desirable to carry out the transesterification until it is almost completed.Substantially completing the transesterification means that even if the transesterification reaction is continued for an additional 2 hours, there will be no labor error. ' indicates a state in which no change in the yield of the target compound represented by the above general formula [deposit] is observed within the range.

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

The target compound represented by the general formula (It) obtained by the reaction of the present invention is separated and purified by conventionally known methods such as distillation and recrystallization.

According to the present invention, flavonecarboxylic acid Nisder, including β-piperidino-ethyl ester of 6-methyl-flavone-8-carboxylic acid, can be produced with high raw material conversion, high yield, and high selectivity. be able to.

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

Example 1 6-Methyl-flavone-8-carboxylic acid methyl ester 5.886E (o
, o2mo/v), β-piperidino-ethanol filter ACJ
Ig (0,024 mol), potassium carbonate 0.276
g (0,002 mo/1/) and 40 ml of dimethylformamide, and 100 ml/1 of dried nitrogen residue.
The reaction was carried out for 12 hours at +00"C while blowing at a minimum of 100 ml. Toluene and water were added to the reaction mixture to separate the layers, and the toluene solution was washed with water, dried, and then concentrated to obtain 6-methyl.
- 7-62 g of β-hyperidinoethyl ester of flavone-8-carboxylic acid (purity 99 by gas chromatography)
・5%) obtained.

On the other hand, the aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, washed with water, dried, and concentrated to yield 6-methyl-flavone-8-carboxylic acid in an amount of 0,+4 g TQ. The conversion rate of methyl ester was 99.4%, the yield of β-piperidino-ethyl ester was 96.8%, the selectivity was 97.4%, and the yield of carboxylic acid was 2.6%.

Examples 2 to 5 The reaction was carried out in the same manner as in Example 1 except that the catalyst listed in Table 1 was used in place of the potassium carbonate in Example 1. The reaction was carried out in the same manner as in Example 1, except that the alcohol listed in Table 2 was used instead, and the results shown in Table 2 were obtained.

Example 14 The reaction was carried out in the same manner as in Example 1, except that the ester listed in Table 3 was used instead of the 6-methyl-flavone-8-carboxylic acid methyl ester in Example 1. The reaction was carried out in the same manner as in Example 1, except that the reaction was carried out under reduced pressure (200+n+nH (< )) instead of blowing, while distilling methanol out of the thread. The conversion rate was 99.8%, and the yield was 97%. .4
%, selectivity was 97.6%, acid yield was 2.4%, and
Suni.

Example 15 The reaction was carried out in the same manner as in Example 1 except that dimethyl sulfur Σj oxide was used in place of dimethylpolamide in Example 1. The conversion rate was 99.6% and the yield was 94.2%.
, the selectivity was 94.6%.

Comparative Examples 1 to 3 The reaction was carried out in the same manner as in Example 1, except that the catalyst shown in Table 4 was used instead of potassium carbonate in Example 1, and the results shown in Table 4 were obtained.

Claims (1)

[Claims] (1) General formula [ID (wherein R1 represents an alkyl group, an aralkyl group, or an aryl group, R2 and R3 each represent hydrogen, an alkyl group, or a halogen, and R4 represents hydrogen, an alkyl group, or an aryl group. ) and alcohols represented by the general formula (1) (wherein R5 represents an aralkyl group, an aralkyl group, a monohydroxyalkyl group or an aminoalkyl group different from R1 above). A method for producing flavonecarboxylic acid esters represented by the general formula (ID (in the formula, R2, R6, R4 and R5 are the same as above) by reacting with the above, characterized in that an alkali metal carbonate is used as a catalyst. A method for producing flavonecarboxylic acid esters.