DK145624B - PROCEDURE FOR PENICILLAMINE OR ITS HOMOLOGIST - Google Patents

Description

/ 57 (19) DENMARK ί®? \ P 'R ^

® (12) PUBLICATION MANUAL (n) 145624 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 5599/72 (51) int.CI.3 C 07 C 149/243 (22) Filing Day 10 · HOV. 1972 (24) Race day 10 · Nov. 1972 (41) Aim. available 16 May 1973 (44) Submitted 3 Jan. 1983 (86) International application no.

(86) International filing day (85) Continuation day - (62) Master application no. -

(30) Priority 15-Nov. 1971 * 2156601, DE

(71) Applicant DEGUSSA AKTIENGESELLSCHAFT, 6000 Frankfurt 1, 'DE.

(72) Inventor Friedrich Asinger, DE: Heribert Offermanns, DE: Karl-

Heinz Gluzek, DE.

(74) International Patent Bureau.

(54) Process for producing penicillamine or its homologue.

The invention relates to a process for the preparation of penicillamine or its homologue by reacting aliphatic aliphatic aliphatic aldehydes with sulfur and ammonia, optionally in the presence of an amine, to triazolines- (3) by converting these thiazolines- (3) of anhydrous hydrogen cyanide to thiazolidine-4-carbonitriles, hydrolysis of the nitriles under the action of mineral acids, the nitriles being first converted at lower temperature to salts of thiazolidine-4-carbonamides and further at elevated temperature to salts of thiazolidine-4- earboxylic acids and ammonium salts, reprocessing of the mixture and separation __j. of the ammonium salts and hydrolytic degradation of the thiazolidine-4-carboxylic acids.

Cd Such a method is described in Danish Patent Application No. 2885/71 (DK Presentation No. 145180).

It has now been found that the preparation of penicillamine or its homologue by such a method is particularly favorable if, according to the invention, thia-

ISLAND

The 2 zolidine-4-carbonitriles for conversion to salts of the thiazolidine-4-carbonamides are introduced into at least 1000 ml of aqueous hydrochloric acid containing at least 30% by weight per mole of nitrile and the conversion is carried out at temperatures from 40 ° to 70 °. ° C. Under these conditions, the hydrolysis proceeds in a relatively short time to obtain better yields than in the previous process, and the thiazolidine-4-carboxylic acid, and thus also the penicillin produced therefrom, is obtained with a higher purity, as illustrated in the comparative examples below.

In particular, it has been found to be convenient for the invention to introduce the thiazolidin-4-carbonitriles to convert to the thiazolidine-4-carbonamide hydrochlorides in 1500 to 3000 ml of the hydrochloric acid per mole of nitrile.

The preparation of thiazolines- (3) by reaction of aliphatic branched aliphatic aldehydes with sulfur and ammonia is carried out in a known manner.

To form the thiazolidine-4-carbonitriles from the thiazolines, the required hydrogen cyanide is used in the gaseous or liquid state, or it is prepared immediately in the reaction mixture by the action of mineral acids, such as concentrated sulfuric acid, on cyanides. The substances may be mixed with each other without the use of solvents or in the presence of organic solvents, especially alkanols such as methanol, ethers such as diethyl ether, aliphatic or aromatic hydrocarbons such as light petrol, or halogenated hydrocarbons such as tetrachloromethane.

The nitriles formed using the usual conditions are separated from the reaction mixture and then subjected to hydrolysis. However, it is also possible to immediately add the reaction mixture to the hydrolysis. This method is particularly suitable when the formation of the nitriles takes place in the absence of organic solvents.

The hydrolysis of the nitriles in aqueous medium takes place at temperatures of 40 ° to 70 ° C, preferably between 50 ° and 60 ° C. It is convenient to mix the acid with the nitrile at approx. 20 ° to 30 ° C and then slowly raise the temperature to 40-70 ° C.

The nitriles or reaction mixtures obtained in the preparation of the nitriles are, for hydrolysis, placed in aqueous hydrochloric acid containing 35 to 38% by weight, but at least 30% by weight of hydrogen chloride. At least 1000 ml per nitrile, especially 1500 to 3000 ml of the hydrochloric acid, is used.

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For the purpose of hydrolysis, the nitriles in the hydrochloric acid, preferably under the exclusion of air, are generally maintained at approx. 6 to 15 hours at temperatures between 40 ° and 70 ° G, and in general in the lower part of this temperature range, approx. 10 to 15 hours and in the upper temperature range necessary with only approx. 6 to 8 hours. By using elevated pressure, times can be somewhat shortened.

From the reaction mixture, the thiazolidine-4-carbonamide hydrochlorides can be separated in the usual manner. They are then absorbed into aqueous mineral acid and become. therein, for conversion to the thiazolidine-4-carboxylic acids, further heated at temperatures of ca. 8CP to 150 ° C by any of the methods of the aforementioned Danish patent application, preferably using an aqueous hydrochloric acid having a hydrogen chloride content of approx. 10 to 15% by weight and advantageously in amounts of ca. 300 ml per moles of carbonamide. In the present case, where an aqueous hydrochloric acid is used to convert the nitriles to the carbonamides, it is desirable that the reaction mixture containing the carbonamides is further heated immediately. In this case, it is not necessary for the nitriles to be completely converted to the carbonamides. For the hydrolysis to the carboxylic acids, the mixture is conveniently heated to boiling, possibly under some elevated pressure, e.g. 3 to 6 at.

The final reaction mixture resulting from the reaction mixture contains the thiazo-lidin-4-carboxylic acids, as salts bound to mineral acids, and ammonium salts. To work up this mixture and to convert the salts of the thiazolidine-4-carboxylic acids to penicillamine or its homologue and to separate the ammonium salts, conventional methods are used.

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

Example 1

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

To 157 g (1 mole) of said 2-isopropyl-5,5-dimethyl-thiazoline (3) was added dropwise 45 ml (1.2 mole) of hydrogen cyanide. The temperature was kept below at 5-10 ° C. Then the mixture was stirred for 1 hour at 5-10 ° C and 3 hours at 20-25 ° C.

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The thus-treated reaction mixture containing the resulting 2-isopropyl-5,5-dimethyl-thiazolidine-4-carbonitrile was introduced into 1500 ml of concentrated hydrochloric acid having a temperature of 20 ° C. This mixture was kept under stirring at 40-45 ° C for 15 hours. On one sample, a shell, calculated on introduced 2-isopropyl-5,5-dimethyl-thiazoline (3), was determined on 76¾ 2-isopropyl-5,5-dimethyl-thiazolidine-4-carbonamide hydrochloride, which showed a decomposition point of 240-242 ° C.

The reaction mixture was immediately heated to boiling temperature, kept at reflux for 8 hours at this temperature and then evaporated to dryness under reduced pressure. From the evaporation residue consisting of 2-isopropyl-2,5-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. 209.5 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride were obtained, corresponding to an exotherm of 87.57, calculated on 2-isopropyl-5,5-dimethyl-thiazoline ( 3) '. The substance, as demonstrated by thin layer chromatography, consisted of a single compound. The compound showed a decomposition point of 210-212 ° C.

Of the 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride thus obtained, 192 g (0.8 mole) was dissolved in 400 ml of warm water and a hot solution of 42 g of sodium carbonate was introduced into this solution. 80 ml of water. The free 2-iso-propyl-5,5-dimethyl-thiazolidine-4-carboxylic acid precipitated thereby. It had m.p. (dec.) 181-183 ° C. The carboxylic acid was then subjected to nitrogen vapor distillation under nitrogen until no longer isobutyraldehyde passed. The distillation residue was evaporated to dryness under nitrogen at reduced pressure. The obtained D, L-penicillamine had m.p. (dec.) 201-202 ° C. Yield 107 g, corresponding to 90% based on thiazolidine-4-carboxylic acid hydrochloride used.

Example 2

The same procedure was used as in Example 1, but the reaction mixture containing 2-isopropyl-5,5-dimethyl-thazolidine-4-carbonitrile was kept in a mixture with 1500 ml of concentrated aqueous hydrochloric acid for 6 hours with stirring at 65-70 ° C. . 187 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride were obtained, corresponding to a yield of 78.2%, based on 2-iso-propyl-5,5-dimethyl-thiazoline used. - (3). The substance showed the same purity as that obtained in Example 1.

Example 3

The same procedure as in Example 1 was used, but the reaction mixture containing 2-isopropyl-5,5-dimethyl-thiazolidine-4-carbonitrile was introduced into 3000 ml of concentrated aqueous hydrochloric acid. This mixture was kept under stirring for 15 hours at 40-45 ° C and then evaporated to dryness under reduced pressure.

5

U562A

The residue was washed with acetone. 210 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carbonamide hydrochloride were obtained, corresponding to a yield of 87.8%, based on 2-isopropyl-5,5-dimethyl-thiazolidine (3) used. The carbonamide hydrochloride contained small amounts of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride. It showed a decomposition point of 238-240 ° C. For further conversion to the carboxylic acid hydrochloride, the substance was dissolved in a mixture of 100 ml of water and 300 ml of concentrated aqueous hydrochloric acid, and this solution was kept refluxed at boiling temperature for 8 hours. The yield of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride was 99%, based on 2-isopropyl-5,5-dimethyl-thiazolidine-4-carbonamide hydrochloride used.

Comparison Examples.

A method according to the invention.

185 g of Raw (95% s) 2-isopropyl-5,5-dimethyl-thiazolidine-4-carbonitrile-di. 0.95 mole of nitrile - was introduced into 1500 ml of concentrated hydrochloric acid which had a temperature of 20 ° C. This mixture was then kept stirring at 40-45 ° G for 15 hours. The reaction mixture was then immediately heated to boiling temperature, refluxed at this temperature for 8 hours and 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 methylene. The methanol was evaporated and the residue was washed with acetone. 209 g of 2-isopropyl-5,5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride were obtained, corresponding to a 92% yield based on 2-isopropyl-5,5-dimethyl-thiazolidine-4-carbonitrile used. The substance was 98% as evidenced by thin layer chromatography. It had a decomposition point of 210-212 ° C.

2, Method according to Danish Patent Application No. 2885/71 (Example 4)

The crude 2-isopropyl-5,5-dimethyl-thiazolidine-4-caronitrile, obtained in 96% yield from the 2-isopropyl-5,5-dimethyl-thiazoline, was dissolved in 5000 ml of methanol. After adding 300 ml of concentrated hydrochloric acid, the solution was gassed with hydrogen chloride for 3 days. The temperature was maintained for the first six hours by cooling at 5 ° C, and during the further course the temperature adjusted without cooling at 35-45pC. 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 at boiling temperature. The reaction mixture was then evaporated to dryness under reduced pressure. From the residue of evaporation that passed