DK145180B - PROCEDURE FOR PENICILLAMINE PREPARATION OR ITS HOMOLOGY OR HYDROCHLORIDES THEREOF - Google Patents

Description

in 145180

The invention relates to a process for the preparation of penicillamine or its homologous or hydrochlorides thereof by reaction of branched aliphatic aliphatic aldehydes with sulfur or sulfur compounds which decompose sulfur under reaction conditions and ammonia or NH 2 NO 2, 2NH of an amine, to thiazolines- (3), conversion of these thiazolines- (3) by anhydrous hydrogen cyanide to thiazoli-din-4-carbonitriles, hydrolysis of the nitriles by hydrochloric acid, and ring cleavage with water vapor.

A process for the preparation of penicillamine is known in which, by reacting isobutyraldehyde with sulfur and ammonia, 2-isopropyl-5,5-dimethyl-thiazoline (3) is converted into hydrogen-cyanide to 2 -isopropyl-5, 5-dimethyl-thiazolidine-1-carbonitrile, which, under oxygen exclusion and hydrochloric acid at temperatures between 70 and 100 ° C, is hydrolyzed to 2-isopropyl-5,5-dimethyl-thiazolidine 4-carboxylic acid hydrochloride which, by hydrolytic degradation, is converted to penicillin hydrochloride (Belgian patent specification no.

738,520). A disadvantage of this process is that the yield and purity of the carboxylic acid obtained by the hydrolysis of the nitrile is not satisfactory, which leads to unsatisfactory yield and purity of the penicillin final product.

There is now provided a process for the preparation of penicillamine or its homologous or hydrochlorides thereof, which process is of the initially specified kind and according to the invention is characterized in that the thiazolidine-4-carbonitriles first act upon hydrochloric acid at from 0 ° to 80 °. ° C is converted to thiazolidine-4-carboxylic acid amide hydrochlorides and, either at temperatures above 80 ° C, under the action of hydrochloric acid, is converted to thiazolidine-4-carboxylic acid hydrochlorides and, under the action of water vapor, to the hydrochlorides. of penicillamine or its homologue, under the action of water vapor, is converted to the amide hydrochlorides of penicillamine or its homologue and under the action of hydrochloric acid at temperatures above 80 ° C is converted to the hydrochlorides of penicillamine or its homologue, and, If desired, a won hydrochloride salt is converted to the corresponding free base.

Thus, in the process of the present invention, the hydrolysis of the thiazolidine-4-carbonitriles is performed stepwise, first providing thiazolidine-4-carboxylic acid amide hydrochlorides. It has been found that in this process, higher yield and purity are obtained for the penicillamine final product, and also for a thiazolidined-4-carboxylic acid hydrochloride prepared from the carboxylic acid amide hydrochloride than is the case in the above known process.

The process is preferably used for the preparation of penicillamine, α-amino-β-mercapto-isovaleric acid. This serves as a feed additive, e.g. for cows or pigs, and as a drug, e.g. in the treatment of Wilson's disease or cystinuria.

To form thiazolines (3), a mixture of preferably stoichiometric amounts of aldehyde and sulfur together with excess ammonia, optionally in the presence of an amine, is heated to 50-100 ° C. The water formed by the reaction is optionally removed by means of a scouring agent which forms with the water an azeotropic mixture. Removing aldehyde is returned to the reaction mixture. The resulting thiazoline- (3) can be recovered in the pure state from the reaction mixture by distillation under reduced pressure and exclusion of air.

As aldehydes, they are considered at the α-carbon atom branched aliphatic aldehydes. For example, isobutyraldehyde leads to penicillamine and α-methyl-butyraldehyde leads to homopenicillamine. Instead of sulfur in elemental form which is preferably used, compounds which degrade sulfur such as polysulfides or compounds of the type 7-phenyl-7-alkyl-amino-8-thioxo-1,2,3 may be used under the reaction conditions. , 4,5,6-hexathiocaner. Ammonia is preferably used in the gaseous state. Instead of ammonia, Di verses solution (ΝΗ ^ ΝΟ, ^, ΖΝΗ ^) can be used. As amines, secondary and tertiary amines are preferably suitable, especially with water immiscible amines, the boiling point of which is between ca. 40 ° C and approx. 150 ° C, e.g. trialkylΙ-ΙΟ amines such as triethylamine, or heterocyclic amines such as pyridine. For each mole of aldehyde, 0.1 to 0.5 mole of amine is used. As the entraining agent for the water formed by the reaction, for example, benzene, cyclohexane or a chlorinated hydrocarbon such as chloroform or the aldehyde itself may be used.

To form the thiazolidine-4-carbonitriles, the thiazoline (3) compounds are treated with excess or preferably about stoichiometric amounts of hydrogen cyanide. For example, for the purpose of the thiazoline-20 (3) compounds, organic solvents, generally alkanols such as methanol, ethers such as diethyl ether, aliphatic or aromatic hydrocarbons such as light petrol, or halogenated hydrocarbons such as tetrachloromethane are added. Hydrogen cyanide is then added to the mixture at temperatures below 10 ° C, after which it is subjected to a post-reaction at room temperature. From this reaction mixture the thiazolidine-4-carbonitriles are separated, the mixture either being cooled to low temperatures, e.g. to below -30 ° C, or the mixture, e.g. by means of a stream of inert gas or under vacuum, the solvent and any excess hydrogen cyanide are freed. The nitriles thus obtained can generally be used immediately for the further processing into carboxylic acids. If necessary, they may optionally be purified by a blend of e.g. hydrocarbons. When the preparation of the nitriles takes place in alkanols as a solvent, the reaction mixture 4 can be immediately fed to the hydrolysis. In this case, the separation of the nine-wheelers is superfluous.

In the process of the invention, the thi-azolidine-4-carbonitriles are first converted to thiazolidine-4-carboxylic acid amide hydrochlorides by the action of 5 hydrochloric acid at 0 ° to 80 ° C. According to the invention, it is suitable to allow the conversion to take place by hydrolysis in concentrated hydrochloric acid at room temperature. For each mole of nitrile, approx. 200 ml, preferably 400-1000 ml 10 concentrated hydrochloric acid.

However, the hydrolysis of the nitriles to carboxylic acid amide hydrochlorides preferably takes place in the presence of organic solvents, especially alkanols such as methanol, at a temperature increasing during the hydrolysis within the range of 0-80 ° C. Thus, according to the invention it is convenient that the conversion of the thiazolidine-4-carbonitriles to thiazolidine-4-carboxylic acid amide hydrochlorides takes place by the thiazolidine-4-carbonitriles, dissolved in alcohol, especially methanol, and in the presence of water, preferably the stoichiometric amount is hydrolyzed by gasification with hydrogen chloride at temperatures initially from 0 ° to 20 ° C and then from 50 ° to 65 ° C.

For each mole of nitrile, 100-1000 ml of alkanol are generally used. The thiazolidine-4-carboxylic acid amide hydrochlorides formed are separated, for example, by evaporation to dryness, and, if necessary, washed with a solvent, preferably acetone.

The 30 thiazolidine-4-carboxylic acid amide hydrochlorides formed by the action of hydrochloric acid on the nitriles are treated in hydrochloric acid at temperatures above 80 ° C for the purposes of the above i) above, hydrolysis to thiazolidine-4-carboxylic acid hydrochlorides. The conversion according to the invention is conveniently carried out by heating in hydrochloric acid to temperatures of approx. 100 ° C, preferably 105 ° C. These temperatures can be obtained by refluxing. For the conversion, according to the invention, aqueous hydrochloric acid having a hydrogen content of 10-15% by weight is suitably used and for each mole of thiazolidine-4-carboxylic acid amide hydrochloride it has been found suitable to use 300-3000 ml, preferably 1000-2000 ml of hydrochloric acid. .

The acidic reaction mixtures formed during the hydrolysis contain thiazolidine-4-carboxylic acid hydrochlorides and ammonium chloride. To reprocess these mixtures and to convert the thiazolidine-4-carboxylic acid hydrochlorides to penicillamine or homologues thereof, neutralization, separation of foreign salts, especially ammonium chloride, and hydrolytic degradation of the ring compound are required. These process steps can be carried out in different ways and in different order. For neutralization, the reaction mixture, preferably after removal of any excess hydrogen chloride, is added to alkaline substances such as alkali metal carbonates or bicarbonates or alkali metal hydroxides. Alien salts are separated, optionally after transfer of the carboxylic acid into a derivative, e.g. in an ester, by the addition of selectively acting solvent, such as water or acetone, or by extraction with such solvents. The ring cleavage is conveniently achieved by a water vapor distillation, optionally carried out in the presence of a small amount of hydrogen chloride.

The described embodiments for working up the carboxylic acids can, if necessary, be combined with each other in other suitable ways. Suitably, a Soxhlet apparatus is used for extraction.

The hydrogen-precipitated, precipitated penicillamine or homologous thereof, optionally bound, is transferred in the usual manner in the free acids, e.g. by treatment with alkali metal hydroxides or bicarbonates or by ion exchangers. In the working processes where penicillin or its homologue or hydrochlorides thereof are formed or present, it may be convenient to exclude air by an inert gas, such as nitrogen.

6 145180

As mentioned under (ii) above, the hydrochlorides of thiazolidine-4-carboxylic acid amide first produced by hydrolysis of the thiazolidine-4-carboxylic acid amide, by circumventing the step of the thiazolidine-4-carboxylic acids 5, can be immediately converted to the amide hydrochlorides of penicillamine or homologous distillate thereof. . These are converted to the hydrochlorides of penicillamine or their homologs thawed a hydrolysis with hydrochloric acid in the same way as the thiazolidine-4-10 carboxylic acid amides to convert to the thiazolidine-4-carboxylic acids, but the reaction must be carried out under inert gas, such as nitrogen. The reaction of the reaction mixture formed by the hydrolysis containing penicillamine or homologous thereof as hydrochlorides and further ammonium salts, and the separation of the ammonium salts can be carried out in the same way as for the different ammonium salts from the thiazolidine-4-carboxylic acids.

For example, the reaction mixture is evaporated to dryness, and the residue is extracted with an alkanol such as methanol or ethanol, or preferably with a water-miscible carbonyl compound, especially acetone. Using a carbonyl compound, it is extracted in hot state, optionally after boiling the evaporation residue in the carbonyl compound, and the extract is boiled with water after evaporation of the carbonyl compound.

The process according to the invention is further described by the following examples.

Example 1

A mixture of 1442 g (20 moles) of freshly distilled isobutyraldehyde free of trimer isobutyraldehyde, 101 g (1 mole) of triethylamine and 320 g (10 moles) of sulfur was gassed with ammonia. The mixture was then kept at boiling temperature and dehydrated azeotropically. The turnover took 7 hours. Within this time, 400 ml of water was removed. At a distillation at reduced pressure of 20 Torr over a column, 1247 g of 2-isopropyl-5,5-dimethyl-thiazoline (3) was obtained from the mixture, corresponding to 79% yield.

In a reflux container supplied with -15 ° C coolant, a mixture of 1573 g (10 moles) of 2-isopropyl-5,5-dimethyl-thiazoline- (3) and 1000 ml of methanol was added. 2 hours fumigated with 300 g (11 moles) of hydrogen cyanide. The temperature of the reaction mixture was kept below by cooling at 5 ° C. After the end of the fumigation, the mixture was left to stand for 4 hours without cooling.

Methanol and excess hydrogen cyanide were then removed at reduced pressure.

To the crude nitrile thus obtained, 4000 ml of concentrated hydrochloric acid was slowly added under cooling. This mixture was left under stirring for 2 days at room temperature, then kept for 2 days at reflux at boiling temperature (105 ° C) and finally evaporated to dryness. To the residue was added 2000 ml of acetone, boiled briefly, cooled and filtered. The 20 yellow colored solid thus obtained contained, in addition to 285 g of ammonium chloride, 1285 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride, corresponding to 53% yield, calculated on the thiazoline used.

59 g of the obtained solid (content of carboxylic acid hydrochloride 0.2 mol) was dissolved in 100 ml of hot water and a solution of 10.6 g of sodium carbonate in 20 ml of water was introduced into this solution. Thereby the free 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid precipitated. When boiling with water, the remaining 30 adhering residues of inorganic salts were removed. The carboxylic acid had a melting point (decomposition point) of 181-183 ° C. The yield was 36.5 g, corresponding to 90%, based on the 2-isopropyl-5,5-dimethyl-thiazo-lidin-4-carboxylic acid hydrochloride used.

40.6 g (0.2 mole) of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid were subjected to nitrogen vapor distillation under nitrogen until no more isobutyraldehyde passed. The distillation residue was evaporated to dryness under nitrogen at reduced pressure and dried further over diphosphorus pentoxide. 28.6 g of pure dl-penicillamine were obtained, corresponding to 96% yield, calculated on the thiazolidine-4-carboxylic acid. This dl-penicilla-5 min had a melting point (decomposition point) of 201-202 ° C.

Example 2

The same procedure was used as in Example 1, but 59 g of the 10 obtained by the hydrolysis of the nitrile (0.2 mole content of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride) was taken up in 100 ml of anhydrous methanol under heating. After cooling, the still undissolved ammonium chloride (9.8 g) was filtered off. The solution was evaporated under reduced pressure. The residue was washed with acetone. 44 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride were obtained with 0.4% ammonium chloride content. Thus, the yield of pure carboxylic acid hydrochloride was 92% of the carboxylic acid hydrochloride contained in the crude product used.

48 g (0.2 mole) of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride were subjected to nitrogen vapor distillation under nitrogen until no isobutyraldehyde was removed. The distillation residue was evaporated to dryness at reduced pressure. 35.4 g of solids were obtained which, for 99.5%, consisted of dl-penicillamine hydrochloride and 0.5% for ammonium chloride, corresponding to 95% yield of dl-penicil-lamin hydrochloride. , calculated on the thiazole-30-di-4-carboxylic acid hydrochloride used.

Example 3

The same procedure was used as in Example 1, but the crude nitrile was dissolved in 5000 ml of methanol. The solution was gassed with hydrogen chloride for 3 days after the addition of 300 ml of concentrated hydrochloric acid. The temperature was kept at 5 ° C for the first 6 hours on cooling, and during the further course the temperature adjusted without cooling to 35-45 ° C. The separated thiazoli-din-4-carboxylic acid amide hydrochloride was filtered off.

The filtrate was evaporated to dryness at reduced pressure.

The residue was washed with 2000 ml of acetone. A total of 2125 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid amide hydrochloride was obtained, corresponding to a yield of 89%, based on the thiazoline used. The thiazolidine-4-carboxylic acid amide hydrochloride had a melting point (decomposition point) of 240-242 ° C.

2124 g (8.9 mol) of 2-isopropyl-5,5-dimethyl-thiazo-lidin-4-carboxylic acid amide hydrochloride were dissolved in a mixture of 1000 ml of water and 3000 ml of concentrated hydrochloric acid, and this solution was kept under reflux for 40 hours. -15 cooling at boiling temperature (105 ° C). A substantial part of the reaction product is separated from the solution by cooling. It was filtered off. From the filtrate, by evaporation to dryness at reduced pressure, the remaining impure part of the product was recovered. The various parts were combined and washed with 3000 ml of acetone. The decolorized substance contained in addition to 450 g of ammonium chloride 2015 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride, corresponding to 84% yield, calculated on 2-isopropyl-5,5-dimethyl-thiazoline- ( 3), and had a melting point (decomposition point) of 211-213 ° C.

The additional work-up was carried out in accordance with the procedure described in Example 1, and to obtain the corresponding yield of dl-penicillamine.

Example 4 47.8g (0.2 mole) of the 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxybic acid amide hydrochloride prepared in Example 3, dissolved in 500 ml of water, was subjected to water vapor distillation under nitrogen. until no more isobutyraldehyde passed. Evaporation residue 35 was evaporated to dryness under nitrogen and at reduced pressure, and the residue was taken up in 100 ml of methanol. Upon addition of 100 ml of diethyl ether, US 180 precipitated penicillamine amide hydrochloride. The yield was 35.8 g, corresponding to 97%, based on the thiazolidine carboxylic acid amide hydrochloride used. The penicillamine amide hydrochloride had a melting point (decomposition point) of 5,233-235 ° C.

18.5 g (0.1 mole) of penicillamine amide hydrochloride was introduced into 100 ml of concentrated hydrochloric acid. This mixture was refluxed at boiling temperature for 40 hours and then cooled and dried to dryness under reduced pressure. All work processes were carried out under nitrogen. A mixture of 4.6 g of ammonium chloride and 16.1 g of penicillamine hydrochloride was obtained. The yield of penicillamine hydrochloride was 87%, based on the penicillamine amide hydrochloride. To separate the ammonium chloride from the penicillamine hydrochloride, the substance was extracted with ethanol.

Example 5 23.8 g (0.1 mole) of one by hydrolysis of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid nitrile, prepared as in Example 1, in the presence of Gene chloride obtained carboxylic acid amide hydrochloride was subjected to water vapor distillation for further hydrolysis. After passing through 6 liters of distillate, the distillation residue was evaporated to dryness 25 at reduced pressure. The penicillamine amide hydrochloride obtained was taken up in 50 ml of concentrated aqueous hydrochloric acid and 100 ml of water and this mixture was kept at boiling temperature for 4 hours. It was then evaporated to dryness under vacuum. The residue was boiled in 100 ml of acetone, freed from acetone by filtration and then boiled for half an hour in 100 ml of water. Then it was evaporated to dryness under reduced pressure to give a mixture of penicillamine hydrochloride and ammonium chloride. This mixture was taken up in 100 ml of anhydrous ethanol. The still undissolved ammonium chloride was filtered off. The filtrate was adjusted to pH 5 between 5 and 6. By the addition of triethylamine dissolved in ethanol, after a short time, picicillamine was separated. The yield of penicillamine was 13.0 g, corresponding to 88%, based on carboxylic acid amide hydrochloride used. The penicillamine had a melting point of 212 ° C.

Example 6

By reaction, as in Example 1, of 787 g (5 moles) of 2-isopropyl-5,5-dimethyl-thiazoline (3) prepared as set forth in Example 1 with 438 g (10 moles) of hydrogen cyanide, 2-isopropyl 5,5-Dimethyl-thiazolidine-4-carbonitrile was taken up in 2000 ml of methanol. To this solution was added 150 ml of concentrated aqueous hydrochloric acid and gassed with hydrogen chloride. The temperature of the solution, which was only 15 ° C, increased in a short time to approx. 65 ° C so that the solution was brought to a boil. Hydrochloride was introduced for 2 hours. The solution was then allowed to stir for 5 hours with stirring. The 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid amide hydrochloride is thereby crystalline. It was filtered off and washed with acetone. An additional portion of the carboxylic acid amide hydrochloride was obtained from the mother liquor by evaporation. This was also washed with acetone. The total yield of carboxylic acid amide hydrochloride was 1035 g. This is 90% based on thiazoline used. The carboxylic acid amide hydrochloride had a melting point (decomposition point) of 240-242 ° C.

Of the 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid amide hydrochloride thus obtained, 239 g (1 mole) was taken up in a mixture of 500 ml of concentrated aqueous hydrochloric acid and 1000 ml of water. The solution was kept at boiling temperature (about 105 ° C) for 4 hours, after which it was cooled and evaporated to dryness under reduced pressure. The product contained 214 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride, corresponding to 35 to 89% yield, based on the carboxylic acid amide hydrochloride used. In the product, by IR spectroscopic examination, carboxylic acid amide hydrochloride could no longer be detected. The additional work-up for penicillin was carried out as described in Example 1 and to obtain corresponding yield.

Example 7 One by reaction as in Example 1 of 787 g (5 moles) of 2-isopropyl-5,5-dimethyl-thiazoline (3), prepared as set forth in Example 1, with 438 g (10 moles) of hydrogen cyanide obtained 2-isopropyl-5,5-dimethyl-thiazolidine-4-carbonitrile was taken up in 2000 ml of methanol. To this solution was added. 150 ml of concentrated aqueous hydrochloric acid was added and hydrogen chloride was gassed. The temperature of the solution, which was only 15 ° C, increased in a short time to approx. 65 ° C so that the solution was brought to a boil. Hydrogen chloride introduction took place for 2 hours.

Then the solution was allowed to stir for 5 hours. The 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid amide hydrochloride is thereby crystalline.

It was filtered off and washed with acetone. A further portion of carboxylic acid amide hydrochloride was obtained from the mother liquor by evaporation. This was also washed with acetone. The total yield of carboxylic acid amide hydrochloride was 1035 g. This is a 90% yield based on thiazoline used. The carboxylic acid amide hydrochloride had a melting point (decomposition point) of 240-242 ° C.

214 g (0.9 mol) of the 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid amide hydrochloride was dissolved in a mixture of 100 ml of water and 300 ml of concentrated hydrochloric acid and this solution was kept at reflux for 40 hours. at boiling temperature (105 ° C). A substantial part of the reaction product is separated by cooling the solution. It was filtered off and from the filtrate, evaporated to dryness under reduced pressure, the remaining impure part of the product was obtained. The various portions were pooled and washed with 300 ml of acetone. The decolorized substance contained, in addition to 45 g of ammonium chloride, 201 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride, corresponding to 93% yield based on the carboxylic acid amide hydrochloride used, and had a melting point (decomposition point) of 211-213 ° C.

The further processing for penicillamine was carried out as indicated in Example 1 and to obtain corresponding yield.

Example 8

By reaction, as in Example 1, of 787 g (5 moles) of 2-isopropyl-5,5-dimethyl-thiazoline (3), prepared as indicated in Example 1, with 438 g (10 moles) of hydrogen cyanide obtained 2-isopropyl -5,5-dimethyl-thiazolidine-4-carbonitrile was taken up in 2500 ml of methanol. The solution was gassed with hydrogen chloride for 3 days after the addition of 150 ml of concentrated hydrochloric acid. The temperature was kept below 5 ° C for the first 6 hours by cooling at 5 ° C and in the further course the temperature adjusted without cooling at 35-45 ° C. The separated thiazolidine-4-carboxylic acid reamide hydrochloride was filtered off. The filtrate was evaporated to dryness at reduced pressure. The residue was washed with 1000 ml of acetone. A total of 1063 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid amide hydrochloride was obtained, corresponding to a yield of 89% based on the thiazoline used. The carboxylic acid amide hydrochloride had a melting point (decomposition point) of 240-242 ° C.

Of the 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid amide hydrochloride thus obtained, 239 g (1 mole) was taken up in a mixture of 500 ml of concentrated aqueous hydrochloric acid and 1000 ml of water. The solution was kept at boiling temperature (105 ° C) for 30 hours, then cooled and evaporated to dryness under reduced pressure. The product contained 214 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride, corresponding to 89% yield based on the carboxylic acid amide hydrochloride used. In the product, by IR spectroscopic examination, carboxylic acid aqueous hydrochloride could no longer be detected. The further processing for penicillamine 14 was carried out as described in Example 1 and to obtain the corresponding yield.

The following two Examples 9 and 10, of which Example 9 is based on the above Example 3, and Example 10 are based on Example 1 of Belgian Patent Specification No. 738,520, are used for direct comparison of the method according to the invention with the prior art. .

Example 9 The crude 2-isopropyl-5,5-dimethylthiazolidine-4-carbonitrile dissolved in 5000 ml of methanol was obtained in Example 1 in 96% yield from 96% of the 2-isopropyl-5,5-dimethyl-thiazoline. After addition of 300 ml of concentrated hydrochloric acid, the solution was gassed for 3 days with hydrogen chloride. The temperature was kept at 5 ° C for the first six hours upon cooling, and during the further course the temperature adjusted without cooling to 35-45 ° C. The separated thiazolidine-4-carboxylic acid amide hydrochloride was filtered off. The filtrate was evaporated to dryness under reduced pressure. The residue was washed with 2000 ml of acetone. The resulting 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid amide hydrochloride was dissolved in a mixture of 1000 ml of water and 3000 ml of concentrated hydrochloric acid, and this solution was kept at reflux for 40 hours at boiling temperature. The reaction mixture was then evaporated to dryness under reduced pressure. From the evaporation residue consisting of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride and ammonium chloride, the carboxylic acid hydrochloride was extracted with methanol. The methanol was evaporated and the residue was washed with acetone. 2015 g of 2-iso-propyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride was obtained, corresponding to a yield of 88%, based on the 2-isopropyl-5,5-dimethyl-thiazolidine-2 used. 4-carbonitrile.

The compound, as demonstrated by thin-length chromatography, had a purity of 97% and had a decomposition point of 211-212 ° C.

Claims (3)

Example 10 Comparative Example. To 184.3 g (1 mole) of 2-Isopropyl-5,5-dimethyl-thiazolidine-4-carbonitrile was added 500 ml of concentrated 5 hydrochloric acid (density 1.19). Then, in the mixture, so much hydrogen chloride was introduced that its consumption corresponded to the formation of hydrochloride. Then, with the passage of a weak stream of nitrogen, approx. 40 hours at 105 ° C (steam room temperature). The reaction mixture was then evaporated to dryness under reduced pressure. From the evaporation residue consisting of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride and ammonium chloride, the carboxylic acid hydrochloride was extracted with methanol. The methanol was evaporated and the residue was washed with acetone. The yield of 2-iso-propyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride, calculated on the 2-isopropyl-5,5-dimethyl-thiazolidine-4-carbonitrile used, was 78%. As shown by thin layer chromatography, the compound had a purity of 89%. 20 PATENT CLAIMS A process for preparing penicillamine or its horologous or hydrochlorides thereof by substituting sulfur or sulfur branched aliphatic aliphatic aldehydes with sulfur or sulfur compounds which decompose sulfur under reaction conditions and ammonia or ΝΗ ^ ΝΟ ^ optionally amine, to thiazolines- (3), conversion of these thiazolines- (3) by anhydrous hydrogen cyanide to thiazolinedin-4-carbonitriles, hydrolysis of the nitriles by hydrochloric acid and ring-splitting with steam, characterized in that thiazolidine-4-carbonitriles -30 ne is first converted to thiazolidine-4-carboxylic acid amide hydrochlorides by the action of hydrochloric acid at 0 ° to 80 ° C and that either i) is converted to thiazolidine-4 at temperatures above 80 ° C under the action of hydrochloric acid. carboxylic acid hydrochlorides and under the action of water vapor 35 are converted into the hydrochlorides of penicillamine or its homologue,