NO153491B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE LITERIC ACID DERIVATIVES. - Google Patents

Description

The present invention relates to an analog method

in the preparation of new therapeutically active threo- or erythro citric acid derivatives with the formula

and the corresponding threo-fi>-lactones with the formula

as well as the pharmaceutically usable salts of these compounds.

The citric acid derivatives of formula Ia and some starting materials

als and intermediate products in the production of these in-

holds two asymmetric carbon atoms and therefore exists in the threo or erythro form. The chlorocitric acid ( h -lactones of formula Ib exist in the threo form. The threo form and the erythro

the form can again exist as racemates or as optical antipodes, the (+) and (-) antipodes. In connection with the treo-ery tr o nomenclature, reference can be made to J. Amer. Chem. Soc,

74, 5828, (1952) and Experientia, 12, 81 (1956).

The terms "alkali metal" and "alkaline earth metal" denote

lithium, sodium and potassium acc. calcium. The term "alka-

nol" refers to an alcohol corresponding to a straight-chain or branched 2Q-al'tan- Examples of alkanols are methanol,

ethanol and 2-propanol.

The compounds with the formulas Ia and Ib and their salts have an anorectic effect and can therefore be used as anorectics in the treatment of obesity in mammals.

The invention relates to a method for the preparation of the compounds with the formulas Ia and Ib and the pharmaceutically usable salts thereof. This method is characterized by the fact that

a) in the preparation of er (+)-threo-lactone of formula Ib, reacts an aqueous solution of a trial alkali metal or

tri-earth alkali metal cis- or -trans-aconitate with chlorine or hypochlorous acid, and reacting the obtained salt of the (+)-threo-chlorocitric acid- -lactone with the formula

where M is an alkali or alkaline earth metal, with an acid, b) in the preparation of a compound of the formula Ia cleaves threo- or erythro epoxyaconic acid with an alkali or alkaline earth metal chloride in an aqueous solvent in the presence of an acid, c) in the preparation of (+)-erythpho-chlorocitric acid with the formula cleaves an epoxide with the formula wherein M' is an alkali metal and R hydrogen or M<1>, with an alkali metal chloride in an aqueous solvent in the presence of an acid, d) in a preparation of (+)-threo-chlorocitric acid of the formula e) if desired, cleaves a obtained (+)-threo-citric acid derivative of formula Ia or Ib or (+)-erythro-citric acid derivative of formula Ia in the optically active antipodes and isolates the desired antipode, f) if desired, isolates an obtained compound of formula Ia or lb i form of a pharmaceutically usable salt.

The aqueous solution from step a), which can be obtained by dissolving aconitic acid in an aqueous solution of an alkali or alkaline earth metal hydroxide, preferably sodium or potassium hydroxide, is cooled to 0 to 30°C, preferably 5°C, and treated with an excess of chlorine or hypochlorous acid, preferably chlorine.

Water or mixtures of water and a lower alkanol, of water and an ether, e.g. dimethoxyethane, tetrahydrofuran or dioxane, or of water and a polar aprotic solvent, such as dimethylacetamide, dimethylformamide, dimethylsulfoxide or hexamethylphosphoramide.

As acids, which are often used in the transfer of the salt Ib^ into the corresponding free acid Ib, mention must be made of mineral acids, such as hydrochloric, sulfuric, nitric or phosphoric acid, sulphonic acids, such as methane-, phenyl- or p-toluenesulphonic acid, and strong organic carboxylic acids, such as trifluoro or trichloroacetic acid.

The hydrolysis of the (2>-lactone function of a dicarboxylic acid of formula Ib or of the disalt thereof of formula Ib^ according to step b) can be achieved by suspending the dicarboxylic acid or the disalt in a volatile solvent that contains the above-mentioned acid or dissolve the therein, and for complete hydrolysis preferably heated to a temperature of 30 to 80°C. A temperature of 50 to 70°C, especially about 70°C, is preferred.

The addition of hypochlorous acid in step a) and the hydrolysis in step

d) can be carried out in stages. Appropriately, however, the disalt Ib^ is acidified and the reaction mixture obtained is heated

for complete hydrolysis of the disalt Ib to (+)-threo-chlorocitric acid. Thus, after completion of the addition of hypochlorous acid, the reaction mixture is preferably acidified with a mineral acid, preferably hydrochloric acid, and heated to complete the transfer of the β-lactone Ib to the acid Ia^ at a temperature of 30 to 100°C, preferably 50 to 90 °C, preferably around 70°C.

The cleavage in step b) is carried out with an alkali or alkaline earth metal chloride in a solvent in the presence of an acid.

Thus (+)-threo-epoxyaconic acid can be cleaved with an alkali metal chloride in an aqueous solvent in the presence of an acid, preferably with an excess of sodium chloride in water in the presence of a molar equivalent of hydrochloric acid, at a temperature between 50 and 80°C , preferably approx. 70°C.

In an analogous way (+)-threo-epoxyaconic acid is cleaved to (-)-threo-chlorocitric acid, (-)-threo-epoxyaconic acid to (+)-threo-chlorocitric acid, (-)-erythro-epoxyaconic acid to (+)-erythro- chlorocitric acid and (+)-erythro-epoxyaconic acid to (-)-erythro-chlorocitric acid by means of an alkali metal chloride in an aqueous solvent in the presence of an acid, preferably an excess of sodium chloride in water in the presence of a molar equivalent of hydrochloric acid, at a temperature between 50 and 80°C, preferably 70°C.

(+)-erythro-chlorocitric acid can be obtained in high yield from (+)-erythro-epoxyaconic acid, as the latter can be produced in situ by epoxidizing cis-aconic acid or its anhydride. The epoxidation is conveniently carried out using hydrogen peroxide and an epoxidation catalyst such as tungstic acid or a salt thereof, preferably an alkali metal salt, preferably the sodium salt. The epoxidation is preferably carried out in water containing up to 2.9 mol equivalent of an alkali metal hydroxide, preferably approx. 2.5 molar equivalents of sodium hydroxide. Instead of water, one can use an organic solvent, such as a lower alkanol or a water-soluble ether, such as dimethoxyethane, tetrahydrofuran or dioxane. The epoxidation is conveniently carried out at a temperature between 0 and 100°C, preferably 20 to 50°C. The formed (+)-erythro-epoxyaconic acid or its salt of formula II can be acidified without isolation and then cleaved with the aid of an alkali metal chloride, preferably sodium chloride. Mineral acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, sulphonic acids, e.g. methane-, phenyl or p-toluenesulphonic acid, and strong organic acids, e.g. trifluoro or trichloroacetic acid. Hydrochloric acid is preferred.

In order to avoid side reactions of the obtained (+)-erythro-chlorocitric acid, the cleavage is preferably carried out in the presence of approx. 1-10 molar equivalents of the acids mentioned further on. When the epoxidation is carried out without an alkali metal hydroxide, approx. 1-10 mole equivalents of acid and when the epoxidation is carried out in the presence of approx. 2.5 mol equivalents of alkali metal hydroxide, approx. 3.5-12.5 mol-equivalents of acid.

The reaction temperature is not critical. The cleavage is nevertheless preferably carried out at a temperature between 50 and 80°C, preferably 70°C.

While in the process described at length above for the production of (+)-erythro-chlorocitric acid Ia^ the starting point is from in situ produced (+)-erythro-epoxyaconic acid, this acid can also be produced as in US patent 3,969,772 and isolate it and then cleave to (+)-erythro-chlorocitric acid, the cleavage being carried out in the same way as for (+)-threo-epoxyaconic acid.

While the optically active citric acid derivatives with the formulas Ia and Ib are conveniently prepared from the optical antipodes of epoxyaconic acid, these compounds can also be prepared by cleavage methods known per se from racemic threo- and ertyhro-citric acid derivatives.

Thus, e.g. (+)-erythro-chlorocitric acid is split using (+)- and (- )-p-nitro-<^-methylbenzamine according to the method described in US patent no. 3,901,915 in the optical antipodes (+) - and (-)-erythro-chlorocitric acid.

The (+)-threo-chlorocitric acid-Q>-lactone can be split according to the methods described further into its optical antipodes. In particular, ( + )-threo-chlorocitric acid ft>-lactone can be reacted

with (+)-p-nitro-(h-methylbenzylamine in a lower alkanol, such as methanol) to the diastereomeric salts of threo-chlorocitric acid - fb -lactone and the salts obtained can be separated in a manner known per se, e.g. e.g. by crystallization.

An advantageous method for the production of (+)-threo-chlorocitric acid Ia^ consists in converting trans-aconic acid into an easily isolable highly crystalline monoalkali metal salt of (+)-threo-epoxyaconic acid and cleaving this as described further on, e.g. with sodium chloride in the presence of hydrochloric acid.

The transfer of trans-aconic acid to the monoalkali metal salt of (+)-threo-epoxyaconic acid can be achieved by various methods.

In a first method, the trans-aconic acid is transferred i

following the method described above in a dialkali metal salt of the (+)-threo-chlorocitric acid-^-lactone. Instead of hydrolysing the fi -lactone as described above directly to the chlorocarboxylic acid Ia^ under acidic conditions, hydrolyses

first the fl -lactone function and at the same time the chlorine function is shifted under alkaline conditions to a trialkali metal salt of (+)-threo-epoxyaconic acid and then the trisalt is transferred by partial hydrolysis into the desired monosalt.

The alkaline induced hydrolysis displacement of the dialkali metal salt of the (+)-threo-chlorocitric acid p, -lactone is carried out with an alkali metal hydroxide, preferably potassium hydroxide, at a temperature between 0 and 40°C, preferably 0 to 25°C.

The partial neutralization of the trisalt of (+)-threo-epoxyaconic acid is carried out by adjusting the pH of the reaction mixture to 7.0-7.5, preferably 7.2, cooling the reaction mixture to -20° to 20°C, preferably 0- 5°C, add 2 molar equivalents of acid and purify the precipitate obtained by recrystallization from water or water-alkanol mixtures. preferably water.

In the second method, the trans-aconic acid is transferred by addition of hypochlorous acid in a trial alkali metal salt of (+)-threo-chlorocitric acid, and this then by cyclization under alkaline conditions and partial neutralization under acidic conditions in a trial alkali metal salt of (+)-threo-epoxy -

aconitic acid.

The addition of hypochlorous acid is carried out by treating the trans-aconitic acid with an alkali metal hypochlorite, preferably potassium hypochlorite, the hypochlorite being prepared by dissolving chlorine in an alkali metal hydroxide solution, preferably aqueous potassium hydroxide. The temperature is not critical, but preferably one works at a temperature between -20° and 20°C, suitably at -5 to 5°C, especially at 0°C. It takes 2 molar equivalents of alkali metal hydroxide to form a dialkali metal salt of trans-aconic acid and then two additional molar equivalents of alkali metal hydroxide to form the necessary alkali metal hypochlorite for addition of hypochlorous acid to the disalt.

The cyclization of the trial alkali metal salt of (+)-threo-chlorocitric acid to the trial alkali metal salt of (+)-threo-epoxyaconic acid is carried out by treating the reaction mixture or the trial alkali metal salt of (+)-threo-chlorocitric acid in a solvent with an alkali metal hydroxide, preferably potassium hydroxide. The cycling temperature is not critical, but preferably one works at a temperature between 15 and 60°C, preferably 25°C. The cyclization is conveniently carried out in a solvent, such as water or a mixture of water and a lower alkanol. preferably water.

The partial neutralization of the trial alkali metal salt of (+)-threo-epoxyconic acid is carried out by treating it, or the reaction mixture in which it was formed, with a mineral acid or an organic acid in a manner analogous to the reaction of the trial alkali metal salt of (+ )-threo described above -chlorocitric acid-(3> -lactone.

In a third method, a variant of the second, approx. two-thirds of a mole-equivalent of trans-aconic acid with approx. 2 molar equivalents of an alkali metal hydroxide, preferably potassium hydroxide, in a solvent, then with approx. one. mole equivalent of alkali metal hypochlorite, preferably potassium hypochlorite, and approx. one-third mole-equivalent of trans-aconic acid to a trial alkali metal salt of (+)-threo-chlorocitric acid.

Water or mixtures of water and lower alkanols, preferably water, can be used as solvent. The temperature is not critical. One still preferably works at a temperature between -20° and 10°C, especially from -10 to

-5°C.

The trisalt thus obtained is transferred in the manner described for the first procedure into the mono-alkali metal salt of (+)-threo-epoxyconic acid.

In the fourth method, (+)-threo-epoxyaconic acid is transferred with approx. one equivalent of an alkali metal hydroxide, preferably potassium hydroxide, in a solvent, such as water or a mixture of water and a lower alkanol, in a monoalkali metal salt, preferably the potassium salt. The temperature is not critical. Nevertheless, one preferably works at a temperature of 5°C. The monosalt obtained is isolated in the same way as for the other variants and purified. The monoalkali metal salts or (+)-epoxy-aconic acid are normally isolated as monohydrates. The (-)-threo-chlorocitric acid can be prepared by neutralizing a monoalkali metal salt of (+)-threo-epoxyaconic acid to (+)-threo-epoxyaconic acid, then cleaving this with (+)-p-nitro-c<-methylbenzylamine to (+)-threo-epoxyaconic acid and cleaves this according to the methods described above to (-)-threo-chlorocitric acid.

The neutralization is conveniently carried out by treating the monoalkali metal salt, preferably the potassium salt, with a strong acid in a solvent. As acid, you can use mineral acids such as hydrochloric acid, hydrogen bromide, nitric acid, perchloric acid and sulfuric acid, and organic acids such as methane-, benzene-, p-toluenesulphonic acid, trifluoro- and trichloroacetic acid. As solvents, water, lower alkanols, mixtures of water and lower alkanols and ketones, such as acetone, methyl ethyl ketone and diethyl ketone, can be used. Mineral acids and ketones, especially sulfuric acid and acetone are preferred.

Of particular interest as anorexics are the compounds of formula Ia and the pharmaceutically usable salts thereof, especially (-)-threo-chlorocitric acid and the pharmaceutically usable salts thereof, due to their better ability to lower pre-consumption compared to hydroxycitric acid and si tronic acid.

Female rats weighing 150-175 g in individual cages are not fed for 48 hours. They are then fed for 5-13 days 3 hours a day with a feed containing 70% glucose. The animals are then given the test substance orally in an aqueous solution 1/2 hour before the 3-hour feeding. After lining, the lining bowls are weighed. The control group consists of 31 animals. Each group treated with a test substance consists of 5-12 rats. The results are shown in Table I.

Female rats with a weight of 130-150 g in individual cages are not given anything for 48 hours. The animals are then fed for 5-12 days 3 hours a day with a feed containing 70% glucose, the test substances are given orally to the animals 1/2 hour before the feeding. The pre-bowls are weighed immediately after the lining. The control group consists of 5-10 animals and the experimental groups of 4-6 animals. The results are shown in Table II.

The citric acid derivatives produced according to the present invention can be used in the form of pharmaceutical preparations, which contain them with an organic or inorganic carrier material suitable for enteral or parenteral application, such as water, gelatin, lactose, starch, magnesium stearate, talc or plant oils. The pharmaceutical preparations may be in conventional form, e.g. in solid form, e.g. as tablets, dragees or suppositories or in liquid form, such as suspensions or emulsions. They can also be processed in conventional form, e.g. are sterilized, and contain conventional pharmaceutical auxiliaries, such as preservatives, stabilizers or emulsifiers, salts to change the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

A pharmaceutical dosage unit may contain 10-1000 mg of (-)-threo-chlorocitric acid or an isomer thereof. The daily parenteral and oral administration dose is 1-150 mg/kg in mammals.

The citric acid derivatives produced according to the present invention can also be mixed with animal additives - premixes - or - concentrates.

The active substance in the pre-premixes or the finished product can be from 0.0025 to 1%, preferably from 0.0625 to 0.40%, especially approx. 0.125% of the daily intake.

EXAMPLE 1

174 g of trans-aconic acid was added portionwise to a stirred solution of 120 g of sodium hydroxide in 400 ml of water. The temperature was maintained at 25°C. After complete dissolution of the acid, the pH value was 7.5.

Approach.

The solution was cooled to 5° and purged with argon. Then, gaseous chlorine was added to the stirred mixture. The temperature was kept at 10-15°. When no more gas was absorbed, the introduction of chlorine was stopped, and the mixture was stirred for 10 minutes at 10°. The mixture was purged of excess chlorine with argon.

The mixture was acidified with 175 ml of concentrated hydrochloric acid and then heated for 1 hour at 70°C, whereby the Q> lactone was hydrolysed. The solution was evaporated to dryness and the residue mixed with ethyl acetate. The combined extracts were filtered and dried. After evaporation of the solvent, the solid was dissolved in ethyl acetate. The solution was diluted with carbon tetrachloride. After stirring and filtering, 102.0 g (+)-threo-chlorocitric acid was obtained, m.p. 96-101°C.

The mother liquors were evaporated to dryness and then crystallized as described above, obtaining a further 60.7 g of pure (+)-threo-chlorocitric acid.

EXAMPLE 2

A solution of 123 g of mono-potassium-(+)-threo-epoxyaconite monohydrate and 28 g of potassium chloride in 120 ml of water was added to 88 ml of concentrated hydrochloric acid. The reaction mixture was heated to 70° for 15 hours, then cooled to room temperature and concentrated. 250 ml of ethyl acetate was added, and the mixture was stirred at 40°. The precipitated potassium chloride was collected and washed with 350 ml of ethyl acetate. The filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate, treated with anhydrous magnesium sulfate and filtered. The filter cake was washed with ethyl acetate. Carbon tetrachloride was added to the filtrate. The mixture was seeded with crystalline (-t-)-threo-chlorocitric acid monohydrate, stirred for 2 hours and stored for 16 hours in a refrigerator. The precipitate was collected, washed with tetrachlorocarbon-ethyl acetate (3:1) and dried to 70.9 g of (+)-threo-chlorocitric acid monohydrate, mp 74-76°C.

The mother liquors were evaporated to dryness. The residue was dissolved in 125 ml of ethyl acetate and treated with carbon tetrachloride, whereby 20.7 g of product is obtained.

A 91.0 g portion of the combined first and second product portions was dissolved in 250 ml of ethyl acetate and treated with 500 ml of carbon tetrachloride. The solution was seeded with crystalline (+)-threo-chlorocitric acid monohydrate and stored overnight in a refrigerator. The precipitate was collected, washed with carbon tetrachloride and ethyl acetate and dried to 84.3 g of pure product, m.p. 74-76°C.

EXAMPLE 3

74.0 g of cis-aconic anhydride was dissolved in 200 ml of water containing 100 g of ice. A solution of 46.25 g of sodium hydroxide in 100 ml of water was added with stirring. The temperature was kept below 20°. It was then successively 15.25

g of sodium tungstate dihydrate and 55.5 ml of 30% hydrogen peroxide added to the mixture. The stirred solution was heated to 23°. The external heat source was removed. At the heat of reaction, the temperature rose within 25 minutes to 51.5° and then began to decrease. After stirring for 30-40 minutes, the mixture was treated with 150 ml of concentrated hydrochloric acid and 150 g of sodium chloride and heated for 15 minutes to 75°. In this way, the intermediate product (+)-erythro-epoxyaconic acid was transferred into (+)-erythro-chlorocitric acid . After cooling the mixture to room temperature, 2.3 g of sodium bisulfate was added to destroy excess hydrogen peroxide. The solution was then extracted continuously with ether.

The first extract was collected after 21 hours, dried and concentrated to 73.0 g of crude chlorocitric acid. Twice recrystallization from ethyl acetate-carbon tetrachloride gave practically pure (+)-erythro-chlorocitric acid, m.p. 162-164°C.

A second extract gave a further 18.5 g of acid, m.p. 163-165°.

EXAMPLE 4

A solution of trisodium trans-aconite, prepared from 58.0 g of trans-aconic acid and 40 g of sodium hydroxide in 300 ml of water, was cooled to 5° and chlorinated as in Example 1. The resulting solution of disodium chlorine in tronic acid-(3>- lactone was purified from excess chlorine and then treated with 60 ml of 12N hydrochloric acid. The mixture was extracted with ethyl acetate and the extracts were purified and dried. The ethyl acetate solution was concentrated and then diluted with carbon tetrachloride. The resulting crystalline material was filtered to give 41.5 g pure (+)-threo-chlorocitric acid-

-lactone, m.p. 162-164°.

EXAMPLE 5

30 g of (+)-erythro-chlorocitric acid were dissolved in 175 ml of a methanol-water mixture (49:1). The solution was cooled to 15° and 39.5 g of (-)-p-nitro-dimethylbenzylamine in 75 ml of the same methanol-water mixture was added. The mixture was stirred at room temperature for 18 hours. The solid was filtered and washed with ethanol and ether, whereby 24.0 g of partially resolved (+)-erythro-chlorocitric acid-bis(-)-p-nitre-ac-methylbenzylamine was obtained. The impure salt was then cleaved in the following manner. Gaseous hydrogen chloride was passed through a stirred suspension of 27.1 g of salt in ether. The resulting solid (-)-p-nitro-O'-methylbenzylamine hydrochloride (19.9 g, m.p. 247-249°) was filtered off and the filtrate concentrated to 10.9 g partially

split (65% optical purity) (+)-erythro-chlorocitric acid in the form of an oil. The (-)-p-nitro-methyl-benzylamine hydrochloride was partitioned between dichloromethane and 1N sodium hydroxide. The amine obtained in this way (15.6 g) was added to 40 ml of methanol-water (49:1) a solution of crude (+)-erythro-chlorocitric acid in 40 ml of methanol-water (49:1). After stirring, 18.1 enriched bis-amino-chlorocitrate was obtained.

The salt was cleaved further with ethereal hydrochloric acid and regenerated as described above, whereby 14.4 g of bis-amine chlorocitrate was obtained. The (+)-erythrochlorocitric acid recovered from the last salt was recrystallized from ethyl acetate-carbon tetrachloride to give 4.3 g (29% chemical yield) of product with 85% optical purity. -The mother liquors in the solution of the partially separated (+)-erythro-chlorocitric acid-bis-(-)-p-nitro-c*,-methylbenzylamine salt were treated with 13 ml of concentrated hydrochloric acid and evaporated. Ether was added to the residue, the mixture stirred and the precipitate collected, whereby 29.2 g of (-)-p-nitro-cX was obtained.

-methylbenzylamine hydrochloride.

The filtrate was evaporated to dryness and the residue enriched in (-)-erythro-chlorocitric acid was dissolved in 90 ml of methanol-water (49:1). A solution of 25.3 g of (+)-p-nitro-O, -methylbenzylamine and 50 ml of methanol-water (49:1) was added. The mixture was stirred for 20 hours and the precipitate collected, whereby 15.0 g of the bis-(+)-p-nitro-methylbenzylamine salt enriched in (-)-erythro-chlorocitric acid was obtained. The salt was suspended in 185 ml of ether and the hydrochloric acid was added to the suspension. The precipitated (+)-p-nitro-C 1 -methylbenzylamine hydrochloride (10.7 g) was filtered. The filtrate was evaporated to dryness and the residue dissolved in 40 ml methanol:water. To the methanol-water solution was added a solution of 8.9 g of (+)-p-nitro-o-methylbenzylamine and 15 ml of methanol-water (49:1) and the solution was stirred for 2.5 hours. The precipitate (11.75 g) enriched in (-)-erythro-chlorocitric acid-bis-(+)-p-nitro-<^ -methylbenzylamine salt was suspended in ether and the suspension was saturated with hydrochloric acid. The precipitated (+)-p-nitro-methylbenzylamine hydrochloride (8.09 g) was collected and the filtrate was concentrated. After crystallization of the residue from ethyl acetate-carbon tetrachloride, 3.9 g were obtained

(-)-erythro-chlorocitric acid (85% optical purity).

EXAMPLE 6

105 g of (+)-threo-epoxyaconic acid monohydrate was dissolved in 150 ml of water containing 43 ml of concentrated hydrochloric acid. 50 g of sodium chloride was added to the stirred solution, and the mixture was heated for 12 hours at 70°. The solution was evaporated to dryness and the residue was mixed with 400 ml of ethyl acetate. The mixture was filtered, and the filtrate was decolorized, dried, and concentrated. The residue was dissolved in 250 ml of ethyl acetate and the solution was treated with carbon tetrachloride. The mixture was stirred for several hours and then cooled. The solid substance was filtered off and 68.5 g of (-)-threo-chlorocitric acid was obtained, m.p. 138-140°, C*)^<5> -6.60 (c, 2.0, H^O). 20.2 g of additional material was obtained from the mother liquors.

EXAMPLE 7

(-)-threo-epoxyaconic acid monohydrate (105 g) was dissolved in 150 ml of water containing 43.0 ml of concentrated hydrochloric acid. To the stirred solution was added 50 g of sodium chloride and the mixture was heated for 12 hours at 70°. When working up the mixture as in example 6, (+)-threo-chlorocitric acid was obtained in two portions:

Portion 1: m.p. 138-140°; (<<>*)p<5> + 6.65°

(c, 2.0, H 2 O); 55.2 g

Portion 2: m.p. 138-140°; «X)^<5> + 6.55°

(c, 2.0, H 2 O); 23.0 g.

By recrystallization of the solid from ethyl acetate-carbon tetrachloride, analytically pure material was obtained, m.p. 140.5-142°; «X)<25>+6<9<o> { c> 20( H^ 0)

EXAMPLE 8

A solution of 8.1 g of (+)-erythro-epoxyaconic acid in 43 ml of hydrochloric acid containing 15 g of sodium chloride was heated for 25 minutes at 78° and 20 minutes at 80°. Evaporation of the solvent gave a residue consisting of crude (-)-erythrochlorocitric acid and sodium chloride. The organic material was dissolved in glyme and the solution was filtered, dried and concentrated. After crystallization of the product from ethyl acetate-carbon tetrachloride, 7.4 g of practically pure (-)-erythrochlorocitric acid was obtained. After recrystallization, 5.4 g of pure acid was obtained, m.p. 133.5-135°; (beer)

2.2° (c, 2.0, H 2 O).

EXAMPLE 9

(-)-erythro-epoxyaconic acid (9.5 g) was transferred into 7.6 g of (+)-erythrochlorocitric acid (m.p. 132-134°) in a manner analogous to example 8. Recrystallization of the chlorocitric acid obtained gave 5.3 g of analytically pure material, m.p. 133.5-135°; ( )<25>+2.2° (c, 2.0, H 2 O).

EXAMPLE 10

87.0 g of trans-aconic acid was added in portions to a solution of 70.0 g of sodium hydroxide in 200 ml of water. The mixture was cooled and chlorinated as in Example 1. The resulting solution of (+)-threo-chlorocitric acid -lactone disodium salt (purified of excess chlorine) was cooled to -10°

and treated with 40.0 g of sodium hydroxide. The solution was stirred, and the mixture on cooling was kept below 20°. The mixture was stirred for 20 minutes at 20°. Then, while cooling, 42 ml of concentrated sulfuric acid was added. The solution was extracted with diethyl ether. The ether extract was dried and concentrated. The resulting solid was crystallized from ethyl acetate-carbon tetrachloride to give 67.8 g of (+)-threo-epoxyaconic acid, m.p. 169-172°. A second portion of 8.85 g, m.p. 167-170° was obtained from the mother liquor.

Claims (2)

1. Analogy method in the preparation of therapeutic active citric acid derivatives with the formula and the corresponding threo-f-lactones with the formula as well as pharmaceutically usable salts thereof, characterized in that a) in the preparation of a (+)-threo-lactone with the formula Ib, an aqueous solution of a trial alkali metal or tri-earth alkali metal cis- or -trans-aconitate is reacted with chlorine or hypochlorous acid , and reacts the obtained salt of (+)-threo-chlorocitric acid-Q>-lactone with the formula wherein M is an alkali or alkaline earth metal, with an acid, b) in the preparation of (+)-threo-chlorocitric acid with the formula hydrolyzes a compound of formula Ib or Ib^, c) in the preparation of a compound of formula Ia cleaves epoxyaconic acid with an alkali or alkaline earth metal chloride in an aqueous solvent in the presence of an acid. d) in the preparation of (+)-erythro-chlorocitric acid with the formula splits a compound with the formula where M' is an alkali metal and R is hydrogen or M', with an alkali metal chloride in an aqueous solvent in the presence of an acid, e) if desired, cleaves an obtained (+)-threo-citric acid derivative of the formula Ia or Ib or (+)-erythro-citric acid derivative of the formula Ia in the optically active avtypes and isolates the desired antipode, f) if desired, isolates an obtained compound of the formula Ia or Ib in the form of a pharmaceutically usable salt. 2. Process according to claim 1, characterized in that (+)-threo-epoxyaconic acid is transferred into (-)-threo-chloro-citric acid.