KR830002160B1 - Process for preparation of citric acid derivatives - Google Patents

Abstract

Citric acid derivatives (I,II,III) were prepd. as the (±)-threo, (+)-threo, and (-)-threo isomers. Thus, tri-sodium-trans-aconitate soln. produced by the mixture of 58.0g transaconitate and 40g sodium hydroxide in 300mL H2O was cooled at 5≰C, and chlorinated. Chlorine gas was removed from the sodium chloro-citric acid-β-lactone soln. and treated with 60mL 12N-HCL. This mixture was extracted with ethyl acetate and dried. This soln. was concentrated, and diluted with carbontetra chloride. 41.5g(±)-threo-chlorocitric acid-β-lactone, which had m.p. 162-164≰C, was obtained.

Description

Method for preparing citric acid derivative

The present invention relates to a novel citric acid derivative of formula (I) and to an optically active colon and a method for preparing a pharmaceutically acceptable salt thereof.

Chloro citric acid of formula (I) is in the form of a treo and can exist in racemates and in two optically-adherents, namely (+)-optical and anti-optic-adducts. In this connection the treo-erythro nomenclature is as defined by J. Amer. Chem Soc, 74, 5828 (1952) and Experientia 12,81 (1956).

In the present specification and claims, "alkali metal" and "alkalito metal" refer to lithium, sodium and potassium and calcium, respectively. "Alkanols" refer to compounds derived by the substitution of hydroxyl groups for both straight and branched chain alkanes having 1 to 20 carbon atoms, examples being methanol, ethanol and 2-propanol.

Structural formula (I) compounds and salts thereof show appetite depleting activity and are useful as appetite reducing agents in the treatment of obesity in mammals.

The compound of formula (I) and pharmaceutically acceptable salts thereof hydrolyze the compound of formula (III) formed by acidifying the compound of formula (II), and the resulting compound of formula (I) is (±)-, ( Prepared in the form of +)-or (-)-form or a pharmaceutically acceptable salt thereof.

Wherein M is an alkali metal or alkaline earth metal.

The starting material of formula (II) dissolves aconitic acid in an aqueous alkali or alkaline earth metal hydroxide solution, preferably in an aqueous sodium or potassium hydroxide solution, and is conveniently cooled to about 0 to 30 ° C, preferably 5 ° C. It can be obtained by treatment with excess chlorine or hypochlorous acid, preferably chlorine.

Suitable aqueous solvents include water and water with lower alkanols, water and ethers (e.g. dimethoxyethane, tetrahydrofuran or dioxane), and water and polar aprotic solvents (e.g. dimethylacetamide, dimethylformamide, dimethylsulfoxide Or hexamethylphosphor amide).

Suitable acids for converting the salts of formula (II) to the corresponding free acids of formula (III) include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, methanesulfonic acid, phenylsulfone or P-toluenesulfonic acid. Strong organic carboxylic acids such as sulfonic acids and trifluoro- or tripoloroacetic acid.

The β-lactone functional group hydrolysis of diacids of formula (III) or of formula (II) disalts is either diacid or in an aqueous solvent containing an acid such as that used to acidify the diacid to the corresponding diacid. This can be accomplished by suspending or dissolving the dichloride and heating the reagent conveniently at about 30-80 ° C. to complete the hydrolysis. Preference is given to a temperature of about 50 to 70 ° C., in particular about 70 °.

Although the chlorohydrination step and the hydrolysis step described above may be carried out stepwise, it is better to acidify the dichloride and heat the resulting reaction mixture to complete hydrolysis of the diacids to obtain (±) -threo-chloro citric acid. Convenient and effective. That is, when chlorohydration is complete, the reaction mixture is preferably acidified with a mineral acid, most preferably hydrochloric acid, and heated to about 30 to 100 ° C., preferably about 50 to 90 ° C., and most preferably about 70 ° C. To complete the conversion of β-lactone (II) to acid (I).

Optically active citric acid derivatives of formula (I) are readily prepared from racemic citric acid derivatives of formula (I) by cleavage methods known in the art.

Of particular interest as appetite reducing agents are the compounds of formula (I) and pharmaceutically acceptable salts thereof, in particular (-)-threo-chloro citric acid and pharmaceutically acceptable salts thereof, as can be seen from the following test results: Likewise, it is much more effective at reducing feed consumption than hydroxy citric acid or citric acid.

Female rats weighing 150 to 175g are placed in a cage for 48 hours and fasted at 70% glucose feed from 8 am to 11 am. After such feed feeding is continued for 5 to 13 days, the appropriate compound is orally administered by intubation 30 minutes before the feeding time. Weigh the feed cup soon after feeding. The control group consists of 31 rats and each drug treatment group consists of 5-12 rats. The results are shown in Table I.

TABLE I

a. Compounds are dissolved in water and administered orally at the indicated concentrations.

b. Each value is the mean value ± standard error.

* p≤0.01

Female rats weighing between 130 and 150 grams are placed in a cage and starved for 48 hours and fed 70% Clucose feed from 8 am to 11 am. Such feeding is continued for 5 to 12 days, and then the appropriate compound is orally administered by intubation 30 minutes before the feeding time. Weigh the feed cup soon after feeding. The control group consists of 5-10 animals, and the experimental group consists of 4-6 animals. The results are shown in Table II.

TABLE II

a. Each value is the mean ± standard error.

* p≤0.05 ** p≤0.001

Citric acid derivatives of the present invention, in addition to the active ingredient, water, gelatin, lactose, starch, magnesium stearate, talc, conventional organic or inorganic inert pharmaceutical auxiliaries, additives and excipients suitable for oral or parenteral administration such as vegetable oil or rubber, etc. It may be formulated into a conventional pharmaceutical formulation containing a carrier material. They are administered in conventional pharmaceutical forms such as tablets, dragees, solid forms such as capsules or suppositories, or liquid forms such as suspensions or emulsions. Pharmaceutical compositions also undergo conventional pharmaceutical procedures such as sterilization, preservatives,

Suitable pharmaceutical dosage units may contain from about 10 to 1000 mg of (-)-threo-chlorocitric acid or isomers thereof. Suitable oral and parenteral doses in mammals are about 1 to 150 mg / kg per day.

The citric acid derivative of the present invention can be administered to animals in admixture with feed additives, premixes or concentrates.

Feed preparation formulations or complete feeds may contain from about 0.0025 to 1.00%, preferably 0.0626 to 0.40%, most preferably about 0.125% of the active ingredient of the daily feed consumption by weight.

Example 1

Preparation of Starting Material

A solution of 120 g of sodium hydroxide dissolved in 400 ml of water is stirred, and 174 g of trans-aconic acid is added thereto. The temperature is kept at 25 ° C. When the acid is completely dissolved, the pH of the solution is 7.5.

The solution is cooled to 5 ° C. and purged with argon.

Pass chlorine gas as quickly as possible to absorb the stirred mixture.

The temperature is kept at 10-15 ° C. When the gas is no longer absorbed, the chlorine gas is stopped and the mixture is stirred at 10 ° C. for 10 minutes. Excess chlorine gas is removed by passing argon gas through the mixed liquid.

Preparation of the product

The reaction solution is acidified using 175 ml of concentrated hydrochloric acid, heated at 70 ° C. for 1 hour to hydrolyze β-lactone. The solution is concentrated to dryness and the residue is triturated with ethyl acetate. The combined extracts are filtered to remove residual sodium chloride and dried. The solvent is evaporated to give a solid which is redissolved in ethyl acetate and diluted with carbon tetrachloride. After stirring, the resulting solid is collected by filtration to give 102.0 g of (±) -threo-chlorocitric acid having a melting point of 96 to 101 占 폚. The mother liquor is concentrated to dryness and crystallized as

Example 2

The resulting trisodium trans-aconitate solution in 58.0 g of trans-aconitic acid and 40 g of sodium hydroxide in 300 ml of water is cooled to 5 ° C. and chlorinated as in Example 1. Excess chlorine gas is removed from this sodium chlorocitric acid-β-lactone solution and treated with 60 ml of 12 N hydrochloric acid. The mixture is extracted with ethyl acetate, and the extracts are combined and dried. The ethyl acetate solution is concentrated and diluted with carbon tetra chloride. The resulting crystalline material was collected by filtration to obtain 41.5 g of pure (±) -threo-chlorocitrate-β-lactone having a melting point of 162 to 164 占 폚.

Claims (1)

A method of preparing a citric acid derivative of formula (I) and an optically active colon thereof, characterized in that the compound of formula (III) or its optically active colon is hydrolyzed in the presence of about 30 to 80 ° C.