FI67073B - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA ITRONSYRADERIVAT OCH MOTSVARANDE TREO-BETA-LAKTONER - Google Patents

Description

---- m Γιι1 nn NOTICE OF PUBLICATION, „n„ VST £ [B] ^ uTLXecNjMQssumpT 670 7 3 (51) KvJiu / iM.a. ^ C 07 C 59/295, C 07 D 305/12 FINLAND — FINLAND (H ) 793976 (W) H »kinl« pUyt — An »Bfci» lnpd »f 18.12.79 (23) aHmHM — 18.12.79 (41) Becoming Public - Blhrtt offantNf 27 Q6 80 P · exam and register managed (44) Nihttvikripano ) · Date of publication - Q 0,

The patent and registration authorities of the United States of America have been published 2o. U9 · 04 (32) (33) (31) Requested brackets — Begird prtorttat 26.12.78 USA (US) 97350 * +, 28.1 1.79 Switzerland-Switzerland (CH) 10580/79 (71) F. Hoffmann-La Roche S Co . Act 1 Schaft, Grenzacherstrasse 12 * + - 18 * +, Basel, Switzerland-Switzerland (CH) (72) Robert William Guthrie, Saddle Brook, NJ, Richard Wightman Kierstead, North Caldwell, NJ, Francis A. Mennona, Nutley, NJ, Ann Clare Sullivan, Cedar Grove, NJ, USA (US) (7 * 0 Oy Koi ster Ab (5 * +) Method for the preparation of therapeutically useful citric acid derivatives i Sten and the corresponding threo - ^ - lactones - Förfarande för fram-ställning av therapeutically anthropogenic citronside and ochelate threo - ^ - lactoner

The invention relates to a process for the preparation of novel citric acid derivatives of the formula Ia and corresponding threo-β-lactones of the formula Ib and their pharmaceutically acceptable salts,

H x 2, CO 2 H HCO 2

^ C1 NC1 OH Ia O. Ib

H02C \ CH2CO2H

The compounds of formulas Ia and Ib and their salts have an anorexic effect and can therefore be used as anorexia agents in the treatment of obesity in mammals.

Compounds of similar structure have been previously described in U.S. Patent Nos. 4,123,458, 4,123,459 and 3,960,933.

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The citric acid derivatives of formula Ia and some of the starting materials and intermediates used in their preparation contain two asymmetric carbon atoms and are therefore in the threo and erythro forms. The chlorositric acid β-lactones of formula Ib are in the threo form. The Treo form and the erythro form, in turn, can be racemates or optical antipodes, (-) and (-) antipodes. In the context of the Treo-erythro nomenclature, reference may be made to "J. Amer. Chem. Soc., 74, 5828 (1952)" and "Experienttia, 12, 81 (1956)".

The terms "alkali metal" and "alkaline earth metal" mean lithium, sodium and potassium or calcium. The term "alcohol" means a straight or branched alcohol corresponding to a C 2-20 alkane. Examples of alcohols are methanol-1, ethanol and 2-propanol.

The compounds of formulas Ia and Ib and their pharmaceutically acceptable salts can be prepared by a) reacting an aqueous solution of a trialkali metal or trima-alkali metal cis- or trans-aconitate with chlorine or alachloric acid and obtaining the (-) - threo-chloroacidate obtained. a salt of a ferric acid β-lactone of the formula

M02C \ ^ H

\ Cl

Ibl M02C / \ / wherein M is an alkali or alkaline earth metal is reacted with an acid to give a (-) - threo-lactone-Tone of formula Ib, or b) hydrolyzing a compound of formula Ib or Ib1 to give (- ) -treo-chlorocitric acid of the formula ho2c | \ C1 OH Ia1

H02C '/ KcH2C02H

or c) cleaving the epoxyaconitic acid with an alkali or alkaline earth metal chloride in an aqueous solvent in the presence of an acid to give a compound of formula Ia, or 3 67073

d) a compound of formula m'o2c H

0 II

M, C

wherein M 'is an alkali metal and R is hydrogen or M', is cleaved with an alkali metal chloride in an aqueous solvent in the presence of an acid to give (-) - erythro-citric acid of the formula H v / ΟΟ, Η N: OH Ia2

H02c / XCH2CO2H

and optionally dividing the obtained (-) - threo-citric acid derivative of formula Ia or Ib or the (-) - erythro-citric acid derivative of formula Ia into optically active antipodes and isolating the desired antipode, and / or modifying the obtained compound of formula Ia or Ib as a pharmaceutically acceptable salt.

In process variant a), the aqueous solution 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 suitably cooled to about 0-30 ° C, preferably 5 ° C, and treated with excess chlorine. or an alchloric acid, preferably with chlorine.

Suitable solvents are water or mixtures of water and a lower alcohol, mixtures of water and ether, e.g. dimethoxyethane, tetrahydrofuran or dioxane, or mixtures of water and a polar aprotic solvent such as dimethylacetamide, dimethylformamide, dimethylsulfoxide or hexamethylphosphoramide.

Suitable acids which can be used to convert the salt Ib1 to the corresponding free acid Ib include, for example, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, sulfonic acids such as methane, phenyl and p-toluenesulfonic acid, and strong organic acids. carboxylic acids such as trifluoroacetic and trichloroacetic acid.

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The hydrolysis of the dicarboxylic acid of the formula Ib or its disalted salt of the formula Ibl according to process variant b) can be carried out by suspending or dissolving the dicarboxylic acid or the disalt in an aqueous solvent containing one of the above acids and heating to complete the hydrolysis. at a temperature of about 30-80 ° C. A temperature of about 50-70 ° C, especially about 70 ° C, is preferred.

The addition of alichloric acid according to process variant a) and the hydrolysis according to process variant b) can be carried out gradually. Suitably, however, the disalt salt Ib1 is acidified and the resulting reaction mixture is heated to complete the hydrolysis of the disaltate Ib to (-) - threochlorous citric acid. Thus, after the addition of alachloric acid, the reaction mixture is acidified, preferably with mineral acid, preferably hydrochloric acid, and / or? To completely convert β-lactone Ib to the acid Ial, it is heated at about 30-100 ° C, preferably at about 50-90 ° C, expediently at about 70 ° C.

The cleavage according to process variant c) is carried out with an alkali or alkaline earth metal chloride in a solvent in the presence of an acid.

(-) - Threo-epoxyaconitic acid can be cleaved with 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 one molar equivalent of hydrochloric acid, at a temperature of about 50-80 ° C, preferably about 70 ° C.

Similarly, (-) - threo-epoxyaconitic acid is cleaved to (-) - threochlorocitric acid, (-) - threo-epoxyaconitic acid to (+) - threo-chloro-citric acid, (-) - erythro-epoxyaconitic acid (+) - erythrachloroacid (+) - Erythro-epoxy-aconitic acid to (-) - erythro-chloro-citric acid by means of an alkali metal chloride in an aqueous solvent in the presence of an acid, preferably in excess of sodium chloride in water with one molar equivalent of hydrochloric acid, at a temperature of about 50-80 ° C, preferably 70 ° C :in.

(-) - Erythro-chlorocitric acid can be obtained in high yield from (-) - erythro-epoxyaconitic acid, the latter being prepared in situ by epoxidation of cis-aconitic acid or its anhydride. The epoxidation is conveniently carried out with hydrogen peroxide and an epoxidation catalyst such as tungstic acid or a salt thereof, preferably an alkali metal salt, suitably a sodium salt. The epoxidation is preferably performed in water containing about 0 to 2.9 molar equivalents of alkali metal hydroxide, preferably about 2.5 molar equivalents of sodium hydroxide. Instead of water, an organic solvent such as a lower alcohol or a water-soluble ether such as dimethoxyethane, tetrahydrofuran or dioxane can be used. The epoxidation is conveniently carried out at about 0-100 ° C, preferably at about 20-50 ° C. The (-) - erythro-epoxyaconitic acid or a salt of formula II formed according to process variant d) can be acidified without isolation and then cleaved with an alkali metal chloride, preferably sodium chloride. As the acid, mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid, sulfonic acids, e.g. methane, phenyl or p-toluenesulfonic acid, and strong organic acids, e.g. trifluoroacetic or trichloroacetic acid, can be used. Hydrochloric acid is preferred.

In order to avoid the side reactions of the obtained (-) - erythro-citric acid, the cleavage is preferably carried out in the presence of about 1 to 10 molar equivalents of one of the above-mentioned acids. If the epoxidation is performed without the use of an alkali metal hydroxide, approximately 1 to 10 molar equivalents of acid are used, and if the epoxidation is performed in the presence of about 2.5 molar equivalents of an alkali metal hydroxide, about 3.5 to 1.25 molar equivalents of acid are used.

The reaction temperature is not critical. However, the cleavage is suitably performed at about 50-80 ° C, preferably at about 70 ° C.

If the process described above for the preparation of (-) - erythro-chlorocitric acid Ia2 starts from (-) - erythroepoxyaconitic acid prepared in situ, this acid can also be prepared and isolated as described in U.S. Patent 3,969,772 and then cleaved to (-) - erythro-citric acid, wherein the cleavage is performed in the same manner as for (-) - threo-epoxyaconic acid.

The optically active citric acid derivatives of the formulas Ia and Ih are conveniently prepared starting from the optical antipodes of epoxyaconitic acid, but can also be prepared using separation methods known per se, starting from racemic threo and erythro citric acid derivatives.

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For example, (-) - erythro-citric acid can be divided into (+) - and (-) - p-nitro-4-methylbenzylamine according to the method described in U.S. Patent 3,901,915 into its optical antipodes, (+) - and (-) erythro-kloorisitruunahapoksi.

(-) - Threo-chlorocitric acid-β-lactone can be divided into its optical antipodes according to the methods described above. In particular, (+) - threo-chlorocitric acid β-lactone can be reacted with (+) - p-nitro-.beta.-methylbenzylamine in a lower alcohol such as methanol to give the diastereomeric salts of threo-chlorositric acid β-lactone and the resulting salts can be separated per se. in a known manner, e.g. by crystallization.

The preferred process for the preparation of (-) - threo-chlorocitric acid Ial is based on the conversion of trans-aconitic acid to an easily isolated, highly crystalline monoalkali metal salt of (+) - threo-epoxyaconitic acid and this is cleaved as described above, e.g. with sodium chloride in the presence of hydrochloric acid.

Conversion of trans-aconitic acid to (-) - threo-epoxyaconitic acid monoalkali metal salt can be accomplished using various methods.

In the first method, the trans-aconitic acid is converted to the dialkali metal salt of (-) - threo-chlorocitric acid β-lactone according to the method described above. Instead of hydrolyzing the 6-lactone as described above directly to the chlorocarboxylic acid under acidic conditions, the?

The basic hydrolysis of the dialkali metal salt of (-) - threo-citric acid / '- lactone is carried out with an alkali metal hydroxide, preferably potassium hydroxide, at a temperature of about 0 to 40 ° C, preferably about 0 to 25 ° C.

Partial neutralization of the trisalt of (-) - threo-epoxyaconic acid is accomplished by adjusting the pH of the reaction mixture to about 7.0-7.5, preferably about 7.2, by cooling the reaction mixture to about -20-20 ° C, preferably about 0- To 5 ° C, adding about 2 molar equivalents of acid and purifying the resulting precipitate by recrystallization from water or water-alcohol mixtures, preferably water.

67073

In another method, trans-aconitic acid is converted by the addition of an alichloroacid to the trial potassium metal salt of (-) - threo-citric citric acid and this is then converted by cyclization under time conditions and partially neutralized under acidic conditions to the trialkali metal salt of (-) - threo-epoxyaconitic acid.

The addition of the alachloric acid is carried out by treating the trans-aconitic acid with an alkali metal hypochlorite, preferably potassium hypochlorite, the hypochlorite being prepared by dissolving the chlorine in an alkali metal hydroxide solution, preferably aqueous potassium hydroxide. The temperature is not critical, but is preferably worked at about -20 to 25 ° C, expediently at about -5 to 5 ° C, especially at about 0 ° C. About 2 molar equivalents of alkali metal hydroxide are required to form the dialkali metal salt of trans-aconitic acid, and then a further two molar equivalents of alkali metal hydroxide are required to form the alkali metal hypochlorite necessary to add the alachloric acid to the disalt.

Cyclization of the trialkali metal salt of (-) - threo-citric acid to the trialkali metal salt of (-) - threo-epoxyaconitic acid is accomplished by treating the reaction mixture or the trialkali metal salt of (-) - threo-citric acid with a alkali metal hydroxide, preferably potassium hydroxide. The cyclization temperature is not critical, but is preferably operated at a temperature between about 15-60 ° C, preferably about 25 ° C. The cyclization is conveniently carried out in a solvent such as water or a mixture of water and a lower alcohol, preferably water.

Partial neutralization of the trialkali metal salt of (-) - threo-epoxyaconitic acid is accomplished by treating it, or the reaction mixture in which it was formed, with a mineral acid or organic acid in a manner similar to the (±) -treo-chloro-citric acid, β-lactone dialkali metal salt described above. .

In the third process, which is a variation of the second process, 2/3 molar equivalent of trans-aconitic acid is reacted with about 2 molar equivalents of alkali metal hydroxide, preferably potassium hydroxide, in a solvent and then with about one molar equivalent of alkali metal hypochlorite, preferably potassium hypochlorite, -equivalent trans-aconitic acid is reacted to give the trialkali metal salt of (-) - threo-chlorocitric acid.

8 67073

As solvents, water and mixtures of water and lower alcohols, preferably water, can be used. Temperature is not critical. However, it is generally preferred to work at a temperature of about -20 to 10 ° C, especially about -10 to -5 ° C.

The tris salt thus obtained is converted into the monoalkali metal salt of (-) - threoepoxyaconic acid as described in the first method.

In a fourth process, (-) - threo-epoxyaconitic acid is converted with approximately one equivalent of an alkali metal hydroxide, preferably potassium hydroxide, in a solvent such as water or a mixture of water and a lower alcohol to a monoalkali metal salt, preferably a potassium salt. Temperature is not critical. However, it is generally preferred to work at a temperature of about 5 ° C. The resulting mono-salt is isolated and purified in the same manner as for the other process alternatives. Mono-alkali metal salts of (-) - epoxy-aconitic acid are usually isolated as monohydrates.

(-) - Threo-chlorocitric acid can be prepared by neutralizing the monoalkali metal salt of (-) - threo-epoxyaconitic acid to (-) - threo-epoxyaconitic acid, which is then separated by (-) - p-nitro-cA-methylbenzylamine (+) - threo-epoxyaconite and this is cleaved to (-) - threo-chlorocitric acid according to the methods described above.

The neutralization is conveniently carried out by treating the monoalkali metal salt, preferably the potassium salt, with a strong acid in a solvent. As the acid, a mineral acid such as hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid and sulfuric acid, and an organic acid such as methane, benzene, p-toluenesulfonic acid, trifluoroacetic and trichloroacetic acid can be used. As solvents, water, lower alcohols, mixtures of water and lower alcohols, 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 anorexia agents are the compounds of formula Ia and their pharmaceutically acceptable salts, in particular (-) - threo-chloro-citric acid and its pharmaceutically acceptable salts, due to their superior ability to hydroxycitric acid and citric acid. reduce food consumption.

9 67073

Female rats weighing 150 to 175 g in different cages are not fed any food for 48 hours. The animals are then fed for 5-13 days 3 hours daily with a diet containing 70% glucose. The animals are then orally administered the test substance in aqueous solution half an hour before feeding for 3 hours. After feeding, the food cups are weighed. The control group consists of 31 animals. Each test substance-treated group consists of 5-12 rats. The results are reported in Table I.

table 1

Concentration Food intake mmol / kg (-) - threo-chloro trisodium (-) - threo-body citric acid hydroxycitrate per well a ^ a% of 9 controls 9 of controls 11.2-0.5 100 11.2-0, 5,100 2.63 3.8-0.3 * 34 8.9-0.8 * 79 1.32 3.1-0.4 * 28 9.9-1.0 88 0.66 3.9- 0.3 * 35 9.0-0.6 * 80 0.33 5.7-0.5 51 11.5-0.7 103 0.17 6.8-0.7 * 61 0.08 6, 4-0.6 57 mean * p - 0.01

Female rats weighing 130-150 g and housed in different cages are not fed any food for 48 hours. The animals are then fed for 5-12 days for 3 hours daily with a diet containing 70% glucose. The test substances are administered orally to the animals half an hour before feeding. Food cups are weighed immediately after feeding. The control group comprises 5-10 animals and the test groups 4-6 animals. The results are reported in Table II.

10

Table II 67073 Treatment Food consumption 2.63 mmol / kg 0.66 mmol / kg body weight per body weight g from control to control

Control 13.5-0.8 100 8.2-1.2 100 citric acid 12.7-1.7 94 ---- --- + * * + (+) - threo-citric acid 5.1-1, 2 38 6.8-1.0 83 + * * + * (-) - threo-chloro-citric acid 2.2-0.5 16 4.8-0.7 59 + * * + (-) - erythro-chloro-citric acid 7 , 2-1, 5 53 7.0-1, 9 85 + * + (+) - erythrochlorocitric acid 10.5-0.8 78 8.1-1.6 99 a mean * p - 0.05 * * p - 0.001

The citric acid derivatives of the formulas Ia and Ib can be used as pharmaceutical preparations containing them together with organic or inorganic carriers suitable for enteral or parenteral administration, such as water, gelatin, lactose, starch, magnesium stearate, talc or vegetable oils. The pharmaceutical preparations may be in conventional form, e.g. in solid form, e.g. in tablets, granules, capsules or suppositories, or in liquid form, such as suspensions or emulsions. They may be treated, e.g. sterilized, in a manner known per se and may contain conventional pharmaceutical auxiliaries, such as preservatives, stabilizers or emulsifiers, salts for varying the osmotic pressure or buffers. They may additionally contain other therapeutically valuable substances.

The pharmaceutical dosage unit may contain about 10 to 1000 mg of (-) - threo-citric acid or one of its isomers. The daily dose of parenteral and oral administration in mammals is about 1-150 mg / kg.

The citric acid derivatives of the formulas Ia and Ib can also be mixed with feed additives, premixtures or concentrates.

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The compound feed or feed may contain about 0.0025 to 1%, preferably about 0.0625 to 0.40%, especially about 0.125% of the daily feed ration of the active ingredient.

Example 1 Preparation of starting material.

174 g of trans-aconitic acid were 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 was 7.5.

Method.

The solution was cooled to 5 ° C and purged with argon. Gaseous chlorine was then introduced into the stirred mixture. The temperature was maintained at 10-15 ° C. When no more gas was absorbed, the chlorine was stopped and the mixture was stirred for 10 min. at 10 ° C. The mixture was purged with excess chlorine under argon.

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

The mother liquors were evaporated to dryness and then crystallized as described above to give an additional 60.7 g of pure (-) - threo-citric acid.

Example 2

To a solution of 123 g of mono-potassium - (-) - threo-epoxy-aconite monohydrate and 28 g of potassium chloride in 120 ml of water were added 88 ml of concentrated hydrochloric acid. The reaction mixture was stirred for 15 hours at 70 ° C, then cooled to room temperature and concentrated. 250 ml of ethyl acetate were added and the mixture was stirred at 40 ° C. 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.

12 67073

The mixture was seeded with crystalline (-) - threo-citric citric acid monohydrate, stirred for 2 hours and stored in a refrigerator for 16 hours. The precipitate was collected, washed with carbon tetrachloride-ethyl acetate (3: 1) and dried to 70.9 g of (-) - threo-chloro-citric acid monohydrate, m.p .: 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 to give 20.7 g of product.

A 91.0 g portion of the combined portions of the first and second products was dissolved in 250 mL of ethyl acetate and treated with 500 mL of carbon tetrachloride. The solution was inoculated with crystalline (-) - threo-citric citric 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-aconitic 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 °. 15.25 g of sodium tungstate dihydrate and 55.5 ml of 30% hydrogen peroxide were then added successively to the mixture. The stirred solution was heated to 23 °. The external heat source was removed. Due to the heat of reaction, the temperature rose for 25 min. inside to 51.5 ° C and then began to decrease. After stirring for 30-40 min. the mixture was treated with 150 ml of concentrated hydrochloric acid and 150 g of sodium chloride and heated for 15 min. at 75 ° C. In this way, the intermediate, (-) - erythro-epoxyaconitic acid, was converted to (-) - erythro-chlorocitric acid. After the mixture was cooled to room temperature, 2.3 g of sodium bisulfite was added to dispose of 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 chloric citric acid. Recrystallization twice from ethyl acetate-carbon tetrachloride gave virtually pure (-) - erythro-citric acid, m.p. 162-164 ° C.

An additional 18.5 acids were obtained from the second extract, m.p. 163-165 ° C.

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Example 4

A solution of trisodium trans-aconitate prepared from 58.0 g of trans-aconitic acid and 40 g of sodium hydroxide in 300 ml of water was cooled to 5 ° C and chlorinated as in Example 1. The disodium chloroacetic acid formed The β-lactone solution was purified from excess chlorine and then treated with 60 ml of 12 N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extracts were combined 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 of pure (-) - threo-chlorocitric acid β-lactone, m.p .: 162-164 ° C.

Example 5 30 g of (-) - erythro-citric acid were dissolved in 175 ml of a methanol-water mixture (49: 1). The solution was cooled to 15 ° C and 39.5 g of (-) - p-nitro-cis-methylbenzylamine in 75 ml of the same methanol-water mixture were added. The mixture was stirred at room temperature for 18 hours. The solids were filtered and washed with ethanol and ether to give 24.0 partially separated bis - (-) - p-nitro-α-methylbenzylamine salt of (+) - erythrochlorocitric acid.

The crude salt was then cleaved as follows. Gaseous hydrogen chloride was bubbled in for 30 min. through a stirred suspension of 27.1 g of salt in ether. The solid (-) - p-nitro-oC-methylbenzylamine hydrochloride formed (19.9 g, m.p. 247-249 ° C) was filtered and the filtrate was concentrated to 10.9 g partially separated (65% optical purity) (+). -erythrochloric citric acid in the form of an oil.

(-) - p-Nitro-α-methylbenzylamine hydrochloride was partitioned between dichloromethane and 1N sodium hydroxide. The amine thus obtained (15.6 g) was added in 40 ml of methanol-water (49: 1) to a solution of crude (+) - erythrochlorocitric acid in 40 ml of methanol-water (49: 1). After stirring, 18.1 g of concentrated bis-amine chlorocitrate were obtained.

The salt was further cleaved with ethereal hydrochloric acid and reconstituted as described above to give 14.4 g of bis-amine chlorocitrate. The (+) - erythrochlorocitric acid from the last salt was recrystallized from ethyl acetate-carbon tetrachloride to give 4.3 g (29% chemical yield) of the product with an optical purity of 85%.

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The mother liquors of the partially separated (+) - erythro-chlorocitric acid-bis - (-) - p-nitro-α-methylbenzylamine salt solution were treated with 13 ml of concentrated hydrochloric acid and evaporated. Ether was added to the residue, the mixture was stirred and the precipitate was collected to give 29.2 g of (-) - p-nitro-cis-methyl-benzylamine hydrochloride.

The filtrate was evaporated to dryness and the residue enriched in (-) - erythro-citric acid was dissolved in 90 ml of methanol-water (49: 1). A solution of 25.3 g of (+) - p-nitro-oC-methyl-benzylamine and 50 ml of methanol-water (49: 1) was added. The mixture was stirred for 20 hours and the precipitate was collected to give 15.0 g of bis- (+) - p-nitro-cis-methylbenzylamine salt, enriched in (-) - erythro-chlorocitric acid. The salt was suspended in 185 ml of ether and hydrochloric acid was added to the suspension. The precipitated (+) - p-nitro-o-methylbenzylamine hydrochloride (10.7 g) was filtered. The filtrate was evaporated to dryness and the residue was dissolved in 40 ml of methanol water (49: 1). To the methanol-water solution were added a solution of 8.9 g of (+) - p-nitro-oL-methylbenzylamine and 15 ml of methanol-water (49: 1), and the solution was stirred for 2.5 hours. The precipitate (11.75 g), enriched with (-) - erythro-chloro-citric acid bis - (+) - p-nitro-oC-methylbenzylamine salt, was suspended in ether and the suspension was saturated with hydrochloric acid. Precipitated (+) - p-nitro-oi! -methylbenzylamine hydrochloride (9, C9 g) was collected and the filtrate was concentrated. After recrystallization of the residue from ethyl acetate-carbon tetrachloride, 3.9 g of (-) - erythrochlorocitric acid (85% optical purity product) are obtained.

Example 6 105 g of (+) - threo-epoxyaconitic acid monohydrate were dissolved in 150 ml of 43 ml of concentrated hydrochloric acid-containing water. To the stirred solution was added 50 g of sodium chloride, and the mixture was heated at 70 ° for 12 hours. The solution was evaporated to dryness and the residue was stirred 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 solids were filtered to give 68.5 g of (-) - threo-citric acid, m.p. 138-140 ° C, δ 6.60 (c, 2.0, H 2 O). An additional 20.2 g of material was obtained from the mother liquor.

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Example 7 (-) - Threo-epoxyaconitic 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 at 70 ° C for 12 hours. Further work-up as described in Example 5 gave (+) - threo-citric acid in two portions:

Part 1: mp: 138-140 °; mp δ + 6.65 ° (c, 2.0, H 2 O); 55.2 g

Part 2: mp: 138-140 °; + 6.55 ° (c, 2.0, H 2 O); 23.0 g.

Recrystallization of the solid from ethyl acetate-carbon tetrachloride gives analytically pure material, m.p. 140.5-142 ° C; Δ δ + 6.9 (c, 2.0, H 2 O).

Example 8

A solution of 8.1 g of (+) - erythro-epoxyaconitic acid in 43 ml of 15 g of hydrochloric acid containing sodium chloride was heated for 25 min. at 78 ° C and 20 min. at 80 ° C. Evaporation of the solvent gave a residue consisting of crude (-) - erythro-citric 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 (-) - erythro-chlorocitric acid were obtained. After recrystallization, 5.4 g of pure acid were obtained, m.p .: 133.5-135 ° C; δ OJp5 -2.2 ° (c, 2.0, H2O).

Example 9 (-) - Erythro-epoxyaconitic acid (9.5 g) was converted to 7.6 g of (+) - erythrochloric citric acid (m.p. 132-134 ° C) in a similar manner as in Example 8. Recrystallization of the obtained chlorocitric acid gave 5.3 g of analytically pure material, m.p. 133.5-135 ° C; β * J 1 + 2.2 (c, 2.0, H 2 O).

Example 10, Preparation of starting material 87.0 g of trans-aconitic acid were added portionwise to a solution of 70.0 sodium hydroxide in 200 ml of water.

The mixture was cooled and chlorinated as described in Example 1. The resulting solution of (+) - threo-chlorositric acid γ-β-lactone disodium salt (purified from excess chlorine) was cooled to 16,67073 -10 ° C and treated with 40.0 g of sodium hydroxide. The solution was stirred and the temperature of the mixture was kept below 20 ° C by cooling. The mixture was stirred for 20 min. at 20 ° C. 42 ml of concentrated sulfuric acid were then added under cooling. The solution was extracted with diethyl ether. The ether extract was dried and concentrated. The solid formed was crystallized from ethyl acetate-carbon tetrachloride to give 67.8 g of (-) - threo-epoxyaconic acid, m.p .: 169-172 ° C. Another portion, 8.85 g, m.p .: 167-170 ° C, was obtained from the mother liquors.

Claims (4)

67073 17 A process for the preparation of therapeutically useful citric acid derivatives of the formula Ia and the corresponding threo, β-lactones of the formula Ib and their pharmaceutically acceptable salts H 1 O 2 CO 2 H 2 O 3 IN 1> 0H Ia / 0. Ib Jc / K y = - ° ho 2 the salt of threo-chlorotin-ferric acid β-lactone of the formula mo2c H "Vei / <% M02C x \ / where M is an alkali or alkaline earth metal is reacted with an acid to give the (-) - threo -lak-Toni, or b) hydrolysing a compound of formula Ib or Ib1 to give (-) - threo-chlorocitric acid of the formula HO 2 Cns ^ * H .Cl OH Ia1 ho 2 c ch 2 co 2 metal chloride in an aqueous solvent in the presence of an acid to give a compound of formula Ia, or 18 d) a compound of formula U / o M'O2C2H2O, O2C / CH2CO2R wherein M1 is an alkali metal and R is hydrogen or M ', is cleaved with alkali metal chloride in an aqueous solvent in the presence of an acid, provided that (-) - Erythro-chlorocitric acid of the formula H 2 O 2 CO 2 H 2 Cl y OH Ia 2 ho 2 O 2 Ch 2 Co 2 H and, if desired, the (-) - threo-citric acid derivative of the formula Ia or Ib or the (-) - erythro the citric acid derivative is divided into optically active antipodes and the desired antipode is isolated, and / or the resulting compound of formula Ia or Ib is converted into a pharmaceutically acceptable salt. Process according to Claim 1, characterized in that the (+) - threo-epoxyaconitic acid is converted into (-) - threo-chlorocitric acid. Paten tkrav 670 7 3 A process for the preparation of a therapeutically active lemon citrate derivative of the formula Ia and a compound of the form of threo -,? (a) in the form of a solution of a (-) - threo-chlorocitrone-cyano-β-lactone in the form of ^ H Cl / V Ib1 color M är en alkali- or jordalkalimetal, omsätts med en syra, varvid erh & lles en (-) - threo-lactone with formula Ib, eller b) en förening med formuleln Ib eller Ib1 hydrolyser, varvid erhälles (- ) -threo-chlorocitrone with formulation HO-C / ° H H02C / \ cH2C02H or c) ) and for the purposes of this Regulation