JPS5825671B2 - Method for producing 5-aroyl-pyrrole glyceryl acetate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 5-aroyl-pyrrole acetate which exhibits anti-inflammatory activity.

The esters are different from the esters of the prior art (see Belgian Patent No. 762,060) in that they have a glyceryl ester function rather than a lower alkyl ester function.

The novel glyceryl ester obtained by the method of the present invention can be structurally represented by the following formula (I).

(However, Ar represents phenyl or lower alkyl-substituted phenyl, and R represents lower alkyl.) As used herein, "lower alkyl" may be linear or branched (, 1 to about can have 6 carbon atoms,
For example, it can be methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and similar alkyls.

The free acid form of formula (I) and its alkali metal salts are described in Belgian Patent No. 762,020 and others.

The salts used herein as starting materials for the preparation of the glyceryl esters that are the subject of the present invention are prepared by converting the corresponding free acid by conventional means, e.g. It can be easily obtained by processing with

React the above alkali metal salt (II) with an inert organic solvent [
For example, by reaction with chloroacetonitrile (III) in dimethyl sulfoxide (DMSO)), the respective cyan methyl ester (■) of pyrolic acid is produced, which is recovered by conventional methods.

For example, the reaction mixture is mixed with water and the resulting precipitate (■) is collected.

If desired, it can also be recrystallized from a suitable solvent (eg acetonitrile).

As used herein, "reaction-inert organic solvent" means (
It means an organic liquid which does not interfere with the reaction of II) and (III) and preferably dissolves the product (IV).

The cyanogen methyl ester (IV) obtained as described above is then treated with a base (e.g. sodium carbonate or potassium carbonate).
The acetone ketal of glycerin (
V).

2,2-dimethyl-1 of each pyrolic acid obtained
- 3-dioxolanyl methyl ester (Vl) is recovered from the reaction mixture in the usual manner.

For example, the reaction mixture is mixed with water, then extracted with a suitable organic solvent (e.g. ether), the organic extract phase is washed with water or brine, the organic extract phase is dried, the solvent is evaporated, and The product (Vl) is mixed with a suitable organic liquid (e.g. lower alkanol such as methanol, ethanol etc.)
It is recovered by treatment with and recrystallization.

Next, this 2,2-dimethyl-1,3-dioxolanyl methyl ester (Vl) was heated (90-
100° C.) to the desired glyceryl ester (■).

When the reaction is complete (approximately 1-2 hours), the acetic acid is evaporated off, the residue is partitioned between water and a good organic solvent for the ester (e.g. ether), and the organic phase is evaporated in the usual manner. Then, the ester (■) is recovered, for example, by evaporating the solvent and recrystallizing the resulting product.

The foregoing reactions can be illustrated in the following reaction sequence.

CX=residue moiety bonded to carboxyl functional group of formula (■)] Glyceryl ester of formula (I) is about 5 to about 250 m9
It has anti-inflammatory activity as shown in the standard kaolin-induced groin edema test (described in Belgian Patent No. 762,060) at doses in the range of 7 kg (body weight).

For example, the most preferred compound 1-methyl-3-(
For p-)luoyl)-pyrrole-2-glyceryl acetate, at a dose of 501n9/kg (body weight) in this study, 26
% inhibition is observed.

Cyan methyl ester of formula (IV) and 2,2-dimethyl-1,3-dioxolanyl methyl ester of formula (■) are also considered new compounds.

These compounds constitute an additional aspect of the invention in that they are useful as precursors for preparing compounds of formula (I).

Next, examples of the present invention will be shown, but these examples are for illustrating the present invention and are not intended to limit the scope of the present invention.

Reference example 1 ■-Methyl-5- (p-)luoyl)-pyrrole-2
-1-methyl-3-(p
-) luoyl)-pyrrole-2-sodium acetate 40
To a suspension of 01111 in dimethyl sulfoxide (DMSO) is added 6.64 P (0,088 mol) of chloracetonitrile all at once.

The mixture is stirred at room temperature for 3.5 hours.

The resulting pale yellow solution is filtered through a sintered glass funnel.

The p solution was injected into water to produce the product 1-methyl-5-(p-
Toluoyl)-pyrrole-2-cyanmethyl acetate is precipitated.

The precipitate is separated by filtration, air-dried and recrystallized from acetonitrile.

Melting point: 131.5-135°C.

Reference Example 2 The operation of Reference Example 1 is repeated to produce cyan methyl ester of formula (IV).

For example, 1-methyl-3-(p-toluoyl) in Example 1
-pyrrole-2-sodium acetate with a suitable formula (I
By using equivalents of the alkali metal salts of I), the following products are obtained in each case:

■-Methyl-3-(p-)luoyl)-pyrrole-2-
15.81 (0,0535 mol) of 1-methyl-5-(
A solution of p-)luoyl)-pyrrole-2-cyanomethyl acetate, 49.51 (0,0376 mol) of acetone ketal of glycerin, and 0.7462 (0,0054 mol) of potassium carbonate was heated at 90°C for 2 hours. do.

After the mixture has cooled, it is poured into water and extracted with ether.

The organic phase is washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulphate and the solvent is evaporated.

A small amount of acetone ketal of glycerin is removed by distillation at 0.4 miHg at steam bath temperature.

By treatment with methanol, the product 1-methyl-
3-(p-Toluoyl)-pyrrole-2-acetic acid 2,2-
Zume 1 chiruto 3-dioxolanylmethyl crystallizes.

The melting point after recrystallization from hexane is 76.5-81°C.

Reference Example 4 According to the procedure of Reference Example 3, 2,2-dimethyl-1,3-dioxolanyl methyl ester of formula (■) can be produced.

For example, by using the equivalent amount of each cyan methyl ester obtained in Reference Example 2 in place of the 1-methyl-3-(p-luoyl)-pyrrole-2-acetate cyanmethyl used in Reference Example 3, the respective corresponding A product of the following formula can be obtained.

1-Methyl-3-(p-toluoyl)-pyrrole-2
-1-methyl-3=(p
A solution of 2,2-dimethyl-1,3-dioxolanylmethyl (-toluoyl)-pyrrole-2-acetate in 45 ml of glacial acetic acid and 187711 water was heated on a steam bath for 3 hours.
Heat for 0 minutes.

The acetic acid is evaporated and the residue is partitioned between ether and water.

The ether phase is separated, washed successively with sodium bicarbonate solution and sodium chloride solution and then dried over anhydrous magnesium sulfate.

Evaporate the solvent. The resulting product 1-methyl-5-(
p-)luoyl)-pyrrole-2-glyceryl acetate from methanol once, ethyl acetate and hexane (1:1)
It is purified by recrystallization four times from a mixture of

Melting point 92-95°C.

Claims (1)

[Scope of Claims] A method for producing glyceryl ester of 5-aroyl-pyrolic acid represented by the formula 1 (wherein Ar represents phenyl or lower alkyl-substituted phenyl, and R represents lower alkyl), comprising: (wherein X is a residue moiety bonded to the carboxyl functional group of formula (I) defined above) A manufacturing method characterized by heating a mixture of the following with an aqueous acetic acid solution.