IE49341B1 - Citric acid derivatives - Google Patents

Abstract

1. Claims for the Contracting States : BE CH DE FR GB IT LU NL SE Monochlorocitric acid derivatives of the formula see diagramm : EP0016867,P13,F3 and the corresponding threo-beta-lactones of the formula see diagramm : EP0016867,P13,F4 and pharmaceutically usable salts of these compounds. 1. Claims for the Contracting State : AT Process for the manufacture of monochlorocitric acid derivatives of the formula see diagramm : EP0016867,P15,F1 and the corresponding threo-beta-lactones of the formula see diagramm : EP0016867,P15,F2 as well as the pharmaceutically usable salts thereof, characterized by a) for the manufacture of a (+-)-threo-lactone of formula Ib, reacting an aqueous solution of a trialkali metal or trialkaline earth metal cis- or trans-aconitate with chlorine or hypochlorous acid and reacting the resulting salt of (+-)-threo-chlorocitric acid beta-lactone of the formula see diagramm : EP0016867,P15,F3 wherein M is an alkali metal or alkaline earth metal, with an acid, b) for the manufacture of (+-)-threo-chlorocitric acid of the formula see diagramm : EP0016867,P16,F1 hydrolyzing a compound of formula Ib or Ib 1, c) for the manufacture of a compound of formula Ia, cleaving epoxyaconitic acid with an alkali metal or alkaline earth metal chloride in an aqueous solvent in the presence of an acid, d) for the manufacture of (+-)-erythro-chlorocitric acid of the formula see diagramm : EP0016867,P16,F2 cleaving a compound of the formula see diagramm : EP0016867,P16,F3 wherein M' represents an alkali metal and R represents hydrogen or M', with an alkali metal chloride in an aqueous solvent in the presence of an acid, e) if desired, resolving a resulting (+-)-threo-citric acid derivative of formula Ia or Ib or (+-)-erythro-citric acid derivative of formula Ia into the optically active antipodes and isolating the desired antipode, f) if desired, isolating a resulting compound of formula Ia or Ib in the form of a pharmaceutically usable salt.

Description

The present invention relates to novel citric acid derivatives of the formulaH\ .co2h x:i la HOgcZ >OH XH2CO2H and corresponding threo-B-lactones of the formula Ib as well as pharmaceutically acceptable salts of these compounds.

The chlorocitric acids of formula la and certain starting materials and Intermediates in the preparation thereof, bear two asymmetric centers and thus exist in two relative stereochemical forms: a threo form and an erythro form. The chlorocitric acid-fi-lactones of formula Ib have the threo form. Each form, i.e. the threo form and erythro form, can exist as a racemate and two optical antipodes, the (+)-optical antipode and the (-)-optical antipode.

In conjunction therewith, the threo-erythro nomenclature as defined in J. Amer. Chem. Soc., 74, 5828 (1952) and Experientia, 12, 81 (1956) has been adopted.

As used throughout the specification and appended claims, the term alkali metal and alkaline earth metal refer to lithium, sodium and potassium, and calcium, respectively. The term alkanol refers to the compound 5 derived by replacement of a proton of a straight or branched chain alkane having 1 to 20 carbon atoms by a hydroxyl moiety. Examples of alkanols include methanol, ethanol and 2-propanol.

The compounds of formulae la and lb and the salts to thereof exhibit anorectic activity and are thus useful as anorectic agents for the treatment of obesity in mammals. The invention relates to the compounds of formulae la and lb and the pharmaceutically acceptable salts thereof as pharmaceutical, particularly anorectic, agents, as well as to pharmaceutical compositions, particularly anorectic compositions, comprising a compound of formula la or lb or a pharmaceutically acceptable salt thereof, and to a process for the manufacture of such compositions.

The invention also relates to a process for the manufacture of the compounds of formulae la and lb and of the pharmaceutically acceptable salts thereof, which process comprises a) for the preparation of a (+)-threo-lactone of formula lb contacting an aqueous solution of a tri-alkali metal its· salt or tri-alkaline earth metal salt of cis- or trans-aoonitic acid with chlorine or hypochlorous acid and contacting the obtained salt of (+)-threo-chlorocitric acid-B-lactone of the formula 9341 MO2C Η ^Cl mo2c lb ι wherein M is an alkali or alkaline earth metal, with an acid, b) for the preparation of (+)-threo-chloroeitrie acid of the formula ho2c -Cl H la 1 :H2CO2H hydrolyzing a compound of formula lb or Ib1, c) for the preparation of a compound of formula la clea ving epoxyaconitic acid with an alkali metal chloride or alkaline earth metal chloride in an aqueous solvent in the presence of an acid, d) for the preparation of (+)-erythro-chlorocitric acid of the formula H, ho2c '«Cl ,OH la 2 -h2co2h cleaving an epoxide of the formula • 49341 wherein M' is an alkali metal and R is hydrogen or M', with in alkali metal chloride in an aqueous solvent in the presence of an acid, e) if desired, resolving an obtained (+)-threo-citric acid derivative of formula la or lb or (t)-erythro-citric acid derivative of formula la into its optically active antipodes and isolating a desired antipode, f) if desiredf isolating an obtained compound of formula la or lb in form of a pharmaceutically acceptable salt thereof.

The aqueous solution of process 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 conveniently cooled to about 0 to 30°C, preferably 5°C, and treated with excess chlorine or hypochlorous acid, preferably chlorine.

Suitable aqueous solvents include water and mixtures of water and a lower alkanol, water and an ether, such as dimethoxyethane, tetrahydrofuran or dioxane, and water and a polar aprotic solvent, such as dimethylacetamide, dimethylformamide, dimethylsulfoxide or hexamethylphosphoramide.

Among acids suitable for the conversion of the salt 48341 Ibl to the corresponding free acid lb may be mentioned mineral acids, e.g. hydrochloric, sulfuric, nitric or phosphoric acid, sulfonic acids, such as methanesulfonic, phenylsulfonic or p-toluenesulfonic acid, and strong orga5 nic carboxylic acids, such as trifluoro- or trichloroacetic acid.

The hydrolysis of the β-lactone function of the diacid of formula lb or the disalt thereof of formula Ib1 according to process step b), can be accomplished by suspending or dissolving the diacid or the disalt in an aqueous solvent containing an acid, such as those employed for the acidification of the disalt Ib1 to the diacid lb, and heating the resulting reaction system, conveniently at a temperature of about 30 to 80°C to complete the hydrolysis. A temperature of about 50 to 70°C, particularly of about 70°C, is preferred.

While the chlorohydrinatlon of step a) and the hy20 drolysis of step b) may be performed stepwise, it is more convenient and efficient to acidify the disalt Ib1 and heat the resulting reaction mixture to complete the hydrolysis of the diacid lb to afford (+)-threo-chlorocitric acid. Thus, upon completion of the chlorohydrination, the reaction mixture is acidified, preferably with a mineral aeid, most preferably hydrochloric acid, and heated from about 30 to 100°C, preferably from about 50 to 90°C, most preferably at about 70°C, to complete the conversion of the β-lactone lb to the acid Ia1.

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

Thus (+)-threo-epoxyaconitic acid may be cleaved by an alkali metal chloride dissolved in an aqueous solvent in the presence of an acid, preferably by excess sodium chloride dissolved in water in the presence of one molar equivalent of hydrochloric acid at a temperature within the range of about 50 to 80°C, most preferably at about 70°C.

Likewise, (+)-threo-epoxyaeonitic acid is cleaved to (-)-threo-chlorocitrlc acid, (-)-threo-epoxyaconitic acid is cleaved to (+)-threo-chlorocitric acid, (-)-erythro-epoxyaconitic acid is cleaved to (+)-erythro-chlorocitric acid and (+)-erythro-epoxyaoonitio acid is cleaved to (-)-erythro-chlorocltric acid by an alkali metal chloride dissolved in an aqueous solvent in the presence of an acid, preferably by excess sodium chloride dissolved in water in the presence of one molar equivalent of hydrochloric acid at a temperature within the range of about 50 to 80°C, most preferably at about 70°C.

(+)-Erythro-chlorocitric acid can be prepared in a high yield process Involving the cleavage of the epoxide ring of (+)-erythro-epoxyaoonitio aoid which can be generated in situ by the epoxidation of ois-aconitio aoid or of the corresponding anhydride. The epoxidation is readily performed utilizing hydrogen peroxide in conjunction with an epoxidation catalyst, e.g. tungstic acid or a salt thereof, preferably an alkali metal salt, most preferably the sodium salt. While the epoxidation is preferably carried out in water, containing about 0 molar equivalents to about 2.9 molar equivalents of an alkali metal hydroxide, preferably about 2.5 molar equivalents of sodium hydroxide, an organic solvent such as lower alkanol or a water soluble ether, suoh as dimethoxyethane, tetrahydrofuran or dioxane, may be employed as a diluent.

The epoxidation is conveniently performed at a temperature of about 0 to 100°C, preferably of about 20 to 50°C. Without isolation, the resulting (+)-erythro-epoxyaoonitio acid or the salt thereof of the formula II can be acidified and then cleaved by treatment with an alkali metal chloride, preferably sodium chloride. Suitable acids include mineral acids, e.g. hydrochloric, sulfuric or phosphoric acid, sulfonic acids, such as methanesulfonic, phenysulfonic or p-toluenesulfonic acid, and strong organic acids, such as trifluoroacetic or trichloroacetic acid. Hydrochloric acid is preferred.

To avoid possible side reactions involving the soformed (+)-erythro-chlorocitric acid, it is desirable to perform the cleavage in the presence of about one to 10 molar equivalents of the abovementioned acids. Thus, when the epoxidation is carried out in the absence of an alkali metal hydroxide, it is desirable to employ about one to about 10 molar equivalents of acid, and when the 15 epoxidation is accomplished in the presence of about 2.5 molar equivalents of alkali metal hydroxide, it is desirable to utilize about 3.5 to 12.5 molar equivalents of acid.

While not narrowly critical, the cleavage reaction temperature is normally maintained within the range of about 50 to 80°C, preferably at about 70°C.

While the afore described process for the preparation 25 of (+)-erythro-chlorocitric acid Ia2 is efficiently performed by cleaving the (+)-erythro-epoxyaconitic acid generated in situ, this acid, prepared and isolated by the method disclosed in the O.S. Patent 3,969,772, may also be cleaved to the erythro-chloroacid as hereinbefore described for the cleavage of (+)-threo-epoxyaconitic acid.

While the optically active citric acid derivatives of formulae la and lb are more readily prepared by chlo< 49341 rinolysis of the oxirane ring of optically active epoxyaconitic acid, as hereinbefore described, these compounds may also be prepared from racemic threo- and erythro-citric acid derivatives by resolution methods known in the art.

For example, by employing (+)-p-nitro-a-methylbenzylamine and (-)-p-nitro-a-methylbenzylamine sequentially as the resolving agents, (+)-erythro-chlorocitric acid may be resolved Into its optical antipodes, (+)erythro-chlorocitric acid and (-)-erythro-chlorocitric acid, by separation of the diastereoisomeric salts so formed, according to the procedure outlined in U.S. Patent 3,901,915.

Further, (+)-threo-chlorocitric acid-B-lactone of formula lb can be resolved into its optically active antipodes by conventional resolving techniques such as set forth in the preceding paragraph. More particularly, (+)threo-chlorocitrlc aoid-fi-lactone can be treated with (+)-p-nitro-a-methylbenzylamine in a lower alkanol, such as methanol, to form the diastereomeric salts of threoohloroditric acid-8-laotone. The salts then are separated by known techniques, such as crystallization.

In an additional and highly efficient synthesis of (+)-threo-chlorocitric acid (Ia1), trans-aconitic acid is converted to a readily isolable and highly crystalline mono-alkali metal salt of (+)-threo-epoxyaconitic acid which is cleaved by the hereinbefore described methods, e.g. with sodium chloride in the presence of hydrochloric acid.

The conversion of trans-aconitic acid to a mono-alkali metal salt of (+)-threo-epoxyaconitio acid may be accomplished by one of several processes. - 9 48341 In the first, trans-aconitic acid is transformed into a di-alkali metal salt of (+)-threo-chlorocitric acidβ-lactone as herein described. Instead of hydrolyzing the β-lactone directly to the chloroacid Ia1 under aci5 die conditions as herein disclosed, it has been found efficacious to first hydrolyze the β-lactone function and concomitantly displace the chloro function to a trialkali metal of (+)-threo-epoxyaconitic acid under alkaline conditions, then partially neutralize the tri10 salt to the desired mono-salt.

The alkali induced hydrolysis - displacement of the dialkali metal salt of (+)-threo-chlorocitric acidβ-lactone is performed with an alkali metal hydroxide, preferably potassium hydroxide, while maintaining the reaction temperature between about 0 to 40°C, more preferably at about 0 to 25°C.

The partial neutralization of the tri-salt of (+)20 threo-epoxyaconitic acid is accomplished by adjusting the pH of the hydrolysis - displacement reaction mixture to a value within the range of about 7.0 to 7.5, preferably to a value of about 7-2, cooling the resulting reaction mixture to a temperature of about -20 to 20°C, preferably 25 to about 0 to 5°C, adding about two molar-equivalents of acid, collecting the precipitate and purifying it by recrystallization from water or water-alkanol mixtures, water being preferred.

In the second process, trans-aconitic acid is ohlorohydrinated to a tri-alkali metal salt of (+)-threochlorocltric acid which is cyclized under alkaline conditions and partially neutralized under acidic conditions to the tri-alkali metal salt of (+)-threo-epoxyaconitic 35 acid.

The chlorohydrination is carried out by treating trans49341 - 10 aconitic acid with an alkali metal hypochlorite, preferably potassium hypochlorite, preformed by the dissolution of chlorine in an alkali metal hydroxide solution, preferably aqueous potassium hydroxide. While the chlorohydrination temperature is not narrowly critical, it is preferred to perform the reaction at a temperature within the range of about -20 to 25°C, more preferably of about -5 to 5°C, most preferably of about 0°C. About two molar-equivalents of alkali metal hydroxide are initially employed to form a di-alkali metal salt of trans-aoonitlc acid and two additional molar-equivalents of alkali metal hydroxide are subsequently employed to form sufficient alkali metal hypochlorite for the hypochlorination of the di-salt.

The cyclization of the tri-alkali metal salt of (+)threo-ohlorocitric acid to the tri-alkali metal salt of (+)-threo-epoxyaconitic acid is accomplished by treating the chlorohydrination reaction mixture or the trialkali metal salt of (+)-threo-chlorocitrio acid, dissolved in a suitable solvent, with an alkali metal hydroxide, preferably potassium hydroxide. The cyclization temperature is not narrowly critical. Nevertheless it is preferred to carry out the reaction at a temperature of about 15 to 60°C, more preferably at about 25°C. Suitable cyclization solvents include water and mixtures of water and lower alkanols. Water is preferred.

The partial neutralization of the tri-alkali metal salt of (+)-threo-epoxyaconitic acid is effected by treating it, or the reaction mixture in which it is derived, with a mineral or organic acid according to the hereinbefore described procedure for the related conversion of the di-alkali metal salt of (+)-threo-chlorocitric acid-6-lactone, In the third process, a variant of the second method, about two-thirds of a molar-equivalent of trans-aconitic - 11 acid is treated with about two molar-equivalents of an alkali metal hydroxide, preferably potassium hydroxide, in an appropriate solvent, followed by about one molarequivalents of preformed alkali metal hypochlorite, pre5 ferably potassium hypochlorite, and about one-third molar-equivalents of trans-aconitic acid to form a tri-alkali metal salt of (+)-threo-chlorooltric acid.

As appropriate solvent there may be mentioned water and mixtures of water and lower alkanols. Water is preferred. While the hypochlorination temperature is not narrowly critical, it is preferable to perform the reaction at a temperature from about -20 to 10°C, more preferably from about -10 to -5°C.

The so obtained tri-salt is transformed to the monoalkali metal salt of (+)-threo-epoxyaconitic acid by the methods hereinbefore described in the description of the first process.

In the fourth process, (+)-threo-epoxyaeonitic acid is converted to its mono-alkali metal salt, preferably the mono-potassium salt, by treatment of the acid with about one equivalent of an alkali metal hydroxide, preferably potassium hydroxide, in a suitable solvent, such as water and mixtures of water and lower alkanols.

It is preferred to carry out the reaction at about 5°C, although the temperature is not critical. The mono-salt so obtained, is isolated and purified as hereinbefore 30 disclosed for the product of the other variants.

The mono-alkali metal salts of (+)-threo-epoxyaconitic acid are generally isolated as the monohydrates.

(-)-Threo-chlorocitric acid may also be prepared by neutralizing a mono-alkali metal salt of (+)-threoepoxyaconitic acid to (+)-threo-epoxyaconitic acid, which - 12 is then resolved into (+)-threo-epoxyaoonitic acid via its bis (+)-p-nitro-a-methylbenzylamine salt and cleaved into (-)-threo-chlorocitrio acid as described hereinbefore.

The neutralization is conveniently performed by treating the mono-alkali metal salt, preferably the potassium salt, with a strong acid in an appropriate solvent. Among strong acids there may be mentioned mineral acids, such as hydrochloric, hydrobromic, nitric, perchloric and sulfuric acid, and organic acids, such as methanesulfonic, benzenesulfonic, p-toluenesulfonic, trifluoroacetlc and trichloroacetic acid. Among appropriate solvents there may be mentioned water, lower alkanols, mixtures of water and lower alkanols and ketones, such as acetone, methylethyl ketone and diethylketone. Mineral acids and ketones, particularly sulfuric acid and acetone, are preferred.

Of particular interest as anorectic agents are the compounds of formula la and the pharmaceutically acceptable salts thereof, more particularly (-)-threo-ohlorocitrio acid and pharmaceutically acceptable salts thereof, which are significantly more active in reducing food consumption than hydroxyoitric acid or citric acid, as can he seen from the following test reports.

Female rats weighing 150 to 175 g,were housed in individual cages, fasted 48 hr, then fed a 70 o/o glucose diet from 8 to 11 a.m. Following 5 to 13 days alimentation, rats were dosed with the appropriate compounds orally by intubation 1/2 hr before the 3 hr meal. Food cups were weighed immediately after the meal. The control group consists of 31 rats while each drug treated group consists of 5 to 12 rats. The results are given in Table I. - 13 •P nJ u +J e a a s o u o Ή CM CO o -H σ> co o +1 o σ» IX o «Η io u Φ 4J -H CM o +1 co © «Η © co IO O -H CO S 4-> TJ c (9 Φ ε Ό CO r— ε ο ο (Ο ΜΙ - 14 Female rats weighing 130 to 150 g, were housed in individual eages, fasted 48 hr, then fed a 70 0/0 glucose diet from 8 to 11 a.m. Following 5 to 12 days alimentation, rats were dosed with the appropriate compounds orally by intubation 1/2 hr before the 3 hr meal. Food cups were weighed immediately after the meal. The control group consisted of 5 to 10 rats, while the experimental group consisted of 4 to 6 rats. The results are given in Table II. - 16 The citric acid derivatives of the present invention can be made up in the form of conventional pharmaceutical preparations containing, in addition to the active ingredients, carrier material, such as conventional organic or inorganic inert pharmaceutical adjuvants, additives and excipients suitable for parenteral or enteral administration, e.g. water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil or gums. They can be administered in conventional pharmaceutical forms, e.g. solid forms, for example tablets, dragees, capsules or suppositories; or in liquid forms, for example suspensions or emulsions. Moreover, the pharmaceutical compositions can be subjected to conventional pharmaceutical expedients, such as sterilization, and can contain conventional pharmaceutical excipients such as preservatives, stabilizing or emulsifying agents, salts for the adjustment of osmotic pressure or buffers. The composition can also contain other therapeutically active materials.

A suitable pharmaceutical dosage unit can contain from about 10 to 1000 mg of (-)-threo-chlorocitrio acid or its isomers. Suitable parenteral and oral dosage regimens in mammals comprise from about 1 to 150 mg/kg per day.

The citric acid derivatives of the present invention can also be compounded with a feed additive, premix or concentrate for administration to an animal.

A feed premix or complete feed can e.g. contain sufficient active ingredient to provide from about 0.0025 to 1.00 o/o, preferably, about 0.0625 to 0.40 o/o, most preferably about 0.125 o/o, by weight of the daily feed consumption. 4934* - 17 Example 1 Preparation of the starting material. 174 g of trans-aconitic 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°.

When the acid had completely dissolved, the solution was at pH 7.5.

The process.

The solution was cooled to 5° and purged with argon. Chlorine gas was then added to the stirred mixture as fast as it could be consumed. The temperature was maintained at 10-15°. When no more gas was absorbed, the addition of chlorine was stopped and the mixture was stirred at 10° for 10 minutes. Excess chlorine gas was purged by bubbing argon gas through the mixture.

The reaction was acidified using 175 ml oonc. hydrochloric acid and then heated at 70° for 1 hour to hydrolyze the β-lactone. The solution was concentrated to dryness and the residue was triturated with ethyl acetate. The combined extracts were filtered to remove residual sodium chloride and then dried. Evaporation of the solvent gave a solid which was redissolved in ethyl acetate. The solution was diluted with carbon tetrachloride. After stirring, the solid which had formed was recovered by filtration to give 102.0 g of (+)-threo-chlorocitric acid, mp 96-101°.

The mother liquors were concentrated to dryness and then crystallized as above to give an addition 60.7 g of pure (+)-threo-chlorooitric acid.

Example 2 To a solution of 123 g of mono-potassium ( + )threo-epoxyaconitic acid monohydrate and 28 g of potassium - 18 chloride in 120 ml of water, was added 88 ml of cone, hydrochloric acid. The reaction mixture was heated at 70° for 15 hours, allowed to cool to room temperature and concentrated. Ethyl acetate (250 ml) was added and the mixture was agitated 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 (+)-threo-chlorocitric aoid monohydrate, stirred for 2 hours and allowed to stand for 16 hours in a refrigerator. The precipitate was collected, washed with carbon tetrachloride-ethyl acetate (3:1) and dried to afford 70.9 g of {+)-threo-chlorocitric acid monohydrate, m.p. 74-76°.

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

A 91.0 g-portion of the combined first and second crops 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 in a refrigerator overnight. The precipitate was collected, washed with carbon tetrachloride and ethyl acetate and dried to yield 84.3 g of purified product, m.p. 74-76°.

Example 3 74.0 g of cis-aconitic anhydride was dissolved in 200 ml of water containing 100 g ice. A solution of 46.25 g of sodium hydroxide in 100 ml of water was added slowly with stirring. The temperature was held below 20°. Then - 19 15.25 g sodium tungstate dihydrate, followed by 55.5 ml of 30 o/o hydrogen peroxide was added to the mixture.

The stirred solution was warmed to 23°. The external heat source was then removed whereupon the heat of reaction caused the mixture temperature to slowly climb to 51.5° over 25 minutes after which it started to decline. After stirring 30-40 minutes, the mixture was treated with 150 ml cone, hydrochloric acid and 150 g sodium chloride and heated at 75° for 15 minutes. In this way the intermediate (+)-erythro-epoxyaconitic acid was converted to (+)-erythro-chloroeitric acid. After the reaction mixture was cooled to room temperature, 2.3 g sodium bisulfite was added to destroy residual hydrogen peroxide. The solution was then continuously extracted using ether.

The first extract collected after 21 hours was dried and concentrated to give 73-0 g of crude chlorocitric acid. Crystallization of this material twice from ethyl acetate-carbon tetrachloride furnished essentially pure (+)-erythro-chlorocitric acid, mp 162-164°.

A second extract gave an additional 18.5 g Of the acid, mp 163-165°.

Example 4 A solution of trisodium trans-aconitate prepared from 58.0 g trans-aconitic acid and 40 g sodium hydroxide in 300 ml of water was cooled to 5° and chlorinated as in 30 Example 1. The resulting solution of disodium chlorocitric acid-S-lactone was purged free of excess chlorine gas and then treated with 60 ml 12N hydrochloric acid. The mixture was extracted with ethyl acetate and the extracts were combined and dried. The ethyl acetate solution was 35 concentrated and then diluted with carbon tetrachloride. The resulting crystalline material was collected by filtration to give 41.5 g of pure (+)-threo- 20 48341 chloroci trio acid-B-lactone, mp 162-164°.

Example 5 g of (+)-erythro-chlorocitric acid was dissolved in 175 ml of a methanol-water mixture (49:1). The solution was cooled to 15° and 39.5 g (-)-p-nitro-a-methylbenzylamine in 75 ml of the same methanol-water mixture was added. The mixture was stirred at room temperatur for 18 hours. The solids were collected by filtration and then washed with ethanol and ether to give 24.0 g of partially resolved (+)-erythro-chlorocitric acid-bis(-)-p-nitro-a-methylbenzylamine salt.

The impure salt was then split in the following manner: hydrogen chloride gas was bubbled through a stirred suspension of finely divided salt (27.1 g) in ether for 30 minutes. The resulting solid (-)-p-nitro-a-methylbenzylamine hydrochloride (19.9 g, mp 247-249°) was removed by filtration and the filtrate was concentrated to give .9 g of partially resolved (+)-erythro-chlorocitric acid as an oil (65 o/o optical purity).

The (-)-p-nitro-a-methylbenzylamine hydrochloride was partitioned between dichloromethane and 1N sodium hydroxide. The amine recovered from this process (15.6 g) in 40 ml methanol-water (49:1) was added to a solution of the crude (+)-erythro-chlorocitric acid in 40 ml methanol-water (49:1) and the mixture, after stirring, deposited 18.1 g of enriohed bis-amine chlorooitrate.

The salt was again split using ethereal hydrogen chloride and was then reformed in the manner described above. This gave 14.4 g of the bis-amine chlorooitrate. The (+)erythro-chloroeitric acid recovered from the latest salt was recrystallized from ethyl acetate-carbon tetrachloride to give 4.3 g of material (29 o/o chemical yield) which - 21 was 85 o/o optically pure.

The mother liquors of the solution of the partially resolved (+)-erythro-chlorocitric acid-bis(-)-p-nitro-a5 methylbenzylamine salt were treated with 13 ml of cone, hydrochloric acid and evaported. 1,2-Dimethoxyethane was added and the solution was evaporated to dryness. Ether was added to the residue, the mixture was stirred and the precipitate was collected to afford 29.2 g of (-)-p10 nitro-a-methylbenzylamine hydrochloride.

The filtrate was concentrated to dryness and the residue, rich in (-)-erythro-chlorocitric acid, was dissolved in 90 ml of methanol-water (49:1). A solution of 25.3 g of (+)-p-nitro-a-methylbenzylamine and 50 ml of methanolwater (49:1) was added. The resulting mixture was stirred for 20 hours and the precipitate was collected to afford 15.0 g of bis-(+)-p-nitro-a-methylbenzylamine salt enriched in (-)-erythro-chlorocitric acid. The salt was suspended in 185 ml of ether and hydrogen chloride was added to the suspension. The precipitated (+)-p-nitro-amethylbenzylamine hydrochloride (10.7 g) was collected on a filter. The filtrate was concentrated to dryness and the residue was dissolved in 40 ml of methanol-water (49:1). To the methanol-water solution was added a solution of 8.9 g of (+)-p-nitro-a-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-chloroeitric acid-bis-(+)-p-nltro-a-methylbenzyl33 amine salt, was suspended in ether and the resulting suspension was saturated with hydrogen chloride. The precipitated (+)-p-nitro-a-methylbenzylamine hydrochloride (3.09 g) was collected and the filtrate was concentrated. Recrystallization of the residue from ethyl aoetate-oar35 bon tetrachloride gave 3-9 g of (-)-erythro-chlorooitrio acid (85 o/o optical purity). * 49341 - 22 Example 6 105 g (+)-threo-epoxyaconitic acid monohydrate was dissolved in 150 ml of water containing 43 ml oono. hydrochloric acid. Sodium chloride (50 g) was added to the stirred solution and the mixture was heated at 70° for 12 hours. The solution was evaporated to dryness and the residue was triturated with 400 ml ethyl acetate. The mixture was filtered and the filtrate was decolorized, dried and concentrated. The residue was dissolved in 250 ml ethyl acetate and the solution was treated with carbon tetrachloride. The mixture was stirred several hours and then chilled. The solids were removed by filtration to give 68.5 g of (-)-threo-ohlorooitric acid, mp 138-140°, [α]ρ5 -6.60° (ο, 2.0, HgO). An additional 20.2 g of material were recovered from the mother liquors.

Example 7 (-)-Threo-epoxyaconitio acid monohydrate (105 g) was dissolved in 150 ml of water containing 43.0 ml cone, hydrochloric acid. To the stirred solution 50 g of sodium chloride was added and the mixture was heated at 70° for 12 hours. The reaction was worked up as in example 6 to give (+)-threo-chlorocitric acid in two crops: crop 1: mp 138-140°; [a]|5 +6.65° (c, 2.0, HgO); 55.2 g crop 2: mp 138-140°; [a]p5 +6.55° (o, 2.0, HgO); 23.0 g.

Recrystallization of the solid from ethyl acetete-carbon tetrachloride gave the analytically pure material, mp 140.5-142°; [a]*5 +6.9° (c, 2.0, H20).

Example 8 A solution of 8.1 g (+)-erythro-epoxyaconitio acid in 43 ml 1N hydrochloric acid containing 15 g. sodium chloride was heated at 78° for 25 minutes and an additional 20 minutes at 80°. Evaporation of the solvent left a residue - 23 consisting of crude (-)-erythro-chlorocitric acid and sodium chloride. The organic material was dissolved in glyme and the resulting solution was filtered to remove sodium chloride, dried and concentrated. Crystallization of the product from ethyl acetate-oarhon tetrachloride afforded 7.4 g of essentially pure (-)-erythro-chlorocitric acid. Recrystallization furnished 5.4 g of pure acid, mp 133-5-135°; [a]^5 -2.2° (c, 2.0, HgO).

Example 9 (-)-Erythro-epoxyaconitio acid (9-5 g) was converted into 7.6 g of (+)-erythro-chlorocitric aoid (mp 132-134°) by a procedure essentially identical to that described in example 8. Recrystallization of the chlorocitric acid thus obtained afforded 5.3 g of analytically pure material, mp 133.5-135°; [a]^5 +2.2° (c, 2.0, H20).

Example 10 Trans-aconitic acid (87.0 g) was added portionwise to a solution of 60.0 g of sodium hydroxide in 200 ml of water. The mixture was cooled and chlorinated as in Example 1. The resulting solution of (+)-threo-ohlorocitric acid-fl-lactone disodium salt (purged free of excess chlorine gas) was cooled to -10° and treated with 40.0 g sodium hydroxide. The solution was stirred and the reaction temperature was moderated by cooling so that it did not exceed 20°. The mixture was stirred at 20° for 20 minutes and then 42 ml of cone, sulfuric acid was added dropwise with cooling. The solution was extracted with diethyl ether. The ether extract was dried and concentrated. The resulting solid was crystallized from ethyl aoetate-carbon tetrachloride to give 67.8 g of (+)-threoepoxyaconitic aoid, mp 169-172°. A second crop (8.85 g; mp 167-170°) was collected from the mother liquors. • 49341 - 24 Example 11 Tablets with the following composition were prepared: (-)-threo-chloroeitric acid polyvinylpyrrolidone microcrystalllne cellulose silicone dioxide 10 magnesium stearate Amount (mq/tablet) 9341

Claims (27)

1. CLAIMS: Citric acid derivatives of the formula K jco 2 h Vc, >OH la ho 2 c h 2 co 2 h and corresponding threo-S-lactones of the formula HOnC. ho 2 c Ya /0=° lb as well as pharmaceutically acceptable salts of these compounds.
2. 2. Compounds according to claim 1 of the formula la and pharmaceutically acceptable salts thereof.
3. 3. (+)-Erythro-chlorocitric acid.
4. 4. (+)-Erythro-chlorocitric acid.
5. 5. (-)-Erythro-chlorocitric acid.
6. 6. (+)-Threo-chlorocitric acid.
7. 7. (+)-Threo-chlorocitric acid. - 49341 - 26
8. 8. (-)-Threo-chlorocitric acid.
9. 9. Compounds according to claim 1 of the formula lb and pharmaceutically acceptable salts thereof.
10. 10. A compound of the group consisting of (+)threo-chlorocitric acid β-laotone, (+)-threo-chlorocitric acid β-lactone and (-)-threo-chlorocitrio acid S-laetone. - 21
11. 11. A compound according to any one of claims 1-10, as pharmaceutically active agent.
12. 12. A compound according to any one of claims 1-10, 5 as anorectic and antiobesity agent.
13. 13. (-)-Threo-chlorocitrio acid as pharmaceutically active agent. 1 θ
14. 14. (-)-Threo-chlorocitric acid as anorectic and antiobesity agent. - 49341 28 15. A process for the manufacture of citric acid derivatives of the formula H. OH la HO 2 C' 'H 2 CO 2 H and of corresponding threo-fi-lactones of the formula lb as well as of pharmaceutically acceptable salts thereof comprising a) for the preparation of a (+)-threo-lactone of formula lb contacting an aqueous solution of a tri-alkali metal salt or tri-alkaline earth metal salt of cis- or trans-aconitic acid with chlorine or hypochlorous acid and contacting the obtained salt of (+)-threo-chlorocitric acid-fi-lactone of the formula •Cl lb 1 wherein M is an alkali or alkaline earth metal, - 29 10 with an acid, b) for the preparation of (+)-threo-chlorocitric acid of the formula H0 2 c H ^Cl ΌΗ ho 2 c //>s ch 2 co 2 h la 1 hydrolysing a compound of formula lb or Ibl,
15. 15. C) for the preparation of a compound of formula la cleaving epoxyaoonitic acid with an alkali metal chloride or alkaline earth metal chloride in an aqueous solvent in the presence of an acid, 20 d) for the preparation of (+)-erythro-chlorocitrio acid of the formula ho 2 c ,co 2 h Cl OH H 2 CO 2 H a2 cleaving a compound of the formula 30 wherein M' is an alkali metal and R is hydrogen or M', - 30 48341 with an alkali metal chloride in an aqueous solvent in the presence of an aoid, e) resolving an obtained (+)-threo-citric acid derivative of formula la or Ib or (+)-erythro-citric acid derivative of formula la into its optically active antipodes and isolating a desired antipode, f) if desired isolating an obtained compound of formula la or Ib In form of a pharmaceutically acceptable salt thereof.
16. 16. A process according to claim 15, wherein (+)threo-epoxyaconitic acid affords (+)-threo-chlorocitric acid.
17. 17. A process according to claim 15, wherein (+)erythro-epoxyacotj^c acid affords (+)-erythro-chlorocitric acid.
18. 18. A process according to claim 15, wherein (+)threo-epoxyaconitic aoid affords (-)-threo-chlorocitric acid.
19. 19. A process according to claim 15, wherein (-)threo-epoxyaconitic acid affords (+)-threo-chlorocitric acid.
20. 20. A process according to claim 15, wherein (-)erythro-epoxyaconitlc acid affords (+)-erythro-chlorocitric acid.
21. 21. A process according to claim 15, wherein (+)erythro-epoxyaconitic acid affords (-)-erythro-chlorocitric acid. - 31
22. 22. Pharmaceutical composition containing a compound of formula la or lb according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof as active ingredient.
23. 23. · Anorectic and antiobesity composition containing a compound of formula la or lb according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof as active ingredient.
24. 24. Pharmaceutical composition containing (-)-threochlorocitric acid as active ingredient.
25. 25. Anorectic and antiobesity composition containing 15 (-)-threo-chlorocitric acid as active ingredient. - 32
26. 26. Compounds of formula la or lb according to any one of claims 1-10 and pharmaceutically acceptable salts thereof, whenever prepared by the process as claimed in any one of claims 15-21 or by an obvious chemical equivalent 5 thereof.
27. 27. , (-)-Threo-chlorooitrio acid, whenever prepared by the process as claimed in claim 15 or 18 or by an obvious chemical equivalent thereof.