CS197093B1 - Process for preparing pure dihydtochloride of triethylentetramine - Google Patents

Description

The invention relates to a process for the preparation of pure triethylenetetramine dihydrochloride from an industrial product having a content of 60 to 80% by weight. triethylenetetramine base.

Triethylenetetramine dihydrochloride (TETA, 2 HCl) is a suitable substitute for penicillamine in the treatment of Villson's disease in those patients in whom penicillamine induces adverse toxic reactions (JMWalshes Lancet 1970 ii k54, Quart. J. Med. Newew. 42 (167), 441). , 1973).

For therapeutic purposes, however, it is necessary to use the salt as pure as possible, for example some 2,2 ', 2-triaminotriethylamine, 1- (2'-aminoethylaminoethyl) piperazine and 4-bis- (2'-aminoethyl) piperazine, which pass into it in the form of hydrochlorides from commercial, commercially available bases are highly toxic (JMWalshes Lancet 1970. ii 154).

The known methods of purification of technical bases are based on their fractionation (RSDubois et al. Lancet 1970 ii 775, G.Sohwarzenbach: Helv.Chim.Acta 33, 974, 1950) and on the fractionated crystallization of TETA.2 HCl (HBPDixon). Lancet 1972 ii 853), optionally utilizing the formation of a crystalline Schiff base of triethylenetetramine with 3 moles of benzaldehyde, included in these operations (van Alphens Rec.Trav.Chim. 55, 415, 1936).

The main disadvantages of these methods are, besides the relatively low yields, a considerable laboriousness and complexity of the equipment (high-vacuum fractionation), which

197,093, however, limit their meaning to the laboratory preparation of small amounts of pure TETA dihydrochloride.

It has been found that pure triethylenetetramine dihydrochloride (as determined by hydromatography) can be used for preparations intended for wedge application, starting from triethylenetetramine tetrahydro chloride obtained from a technical product containing 60 to 80% by weight of triethylenetetramine. % of triethylenetetramine base and, if the process according to the invention is carried out, characterized in that the starting technical product is first neutralized with 15 to 20% by weight of hydrochloric acid, then by adding 6 to 24% by weight of concentrated hydrochloric acid. parts, based on 1 wt. of crystalline triethylenetetramine tetrahydrochloride which is isolated and from which, after optional recrystallization, 2 moles of hydrogen chloride are removed by treatment with a base of the reagent, preferably an alkali metal hydroxide or alcoholate or an anion exchange resin in the OH-ring.

The use of crystalline triethylenetetramine tetrahydro chloride as an intermediate for the preparation of chromatographically pure triethylenetetramine dihydrochloride compounds suitable for clinical application is particularly advantageous in that said salt is very poorly soluble in concentrated aqueous hydrochloric acid and methanol, or mixtures thereof, under undesirable conditions under suitable conditions. impurities, including 1- (2'-aminoethyl-aminoethyl) piperazine (whose dihydrochloride is difficult to separate from fractionated cryetalizaol from TETA dihydrochloride), remain in the mother liquors, even if they are present in large quantities in the starting mixture at 20-40%. A further advantage of the process according to the invention over the prior art methods is the substantially higher yields, less effort and the possibility of implementation on conventional apparatuses of the chemical industry. Nor is it negligible that TETA tetrahydrochloride, as an intermediate against TETA dihydrochloride, is substantially more stable, not so easily decomposed in air by light and heat. Therefore, the pure can be prepared in large quantities and processed to the TETA dihydrochloride in one operation, successively in smaller portions as needed.

In carrying out the process according to the invention, it is expedient to proceed by starting the technical product with a content of 60 to 80% by weight. the triethylenetetramine base is first neutralized with a 15-20% aqueous hydrochloric acid solution. Concentrated hydrochloric acid is then added from this solution, generally in an amount of 6 to 24 wt. parts, based on 1 wt. part of the starting Teohnlo product precipitates crystalline TETA tetrahydrochloride. This procedure can also be varied by crystalline tetrahydrochloride upon initial neutralization (by addition of a mixture of concentrated hydrochloric acid and methanol, and the crude product obtained is purified by crystallization of aqueous methanol.

Another possibility to quickly get rid of the undesirable impurities accompanying triethylenetetramine in the TeOH base is to react with benzaldehyde to form the Schiff base of the formula

CgHjCH - NCHgCHg

197 093, which is precipitated in crystalline form and whose decomposition with concentrated hydrochloric acid and temperature increase gives crystalline tetrahydro chloride TETA, suitable for the preparation of pure dihydro chloride TETA in the next step.

This step can be accomplished in several ways: The first is to remove 2 moles of hydrogen chloride using a sodium alcoholate solution, such as methylate, and the reaction is then carried out in methanol, the second is using an alcoholic solution of an alkali metal hydroxide such as sodium hydroxide in ethanol. . The third way is to use an anion exchange resin in an OH-cycle, which is contacted with an aqueous solution of pure tetrahydrochloride TETA, the treated solution is evaporated and the residue is recrystallized from anhydrous ethanol.

Further details of the process according to the invention can be seen from the following examples, which are illustrative but not limiting.

Example 1

To the mixture 20 ml cono. hydrochloric acid and 20 ml of water are added dropwise, while cooling and stirring, 5.0 g of triethylenetetramine technical base (TETA). The solution was then treated with 50 ml at a time. conc. hydrochloric acid and the crystalline product precipitated after standing for 2 hours at room temperature are filtered off with suction, washed twice with 10 ml of conc. hydrochloric acid and dried to constant weight in a desiccator over solid sodium hydroxide. 5.10 g of TETA tetrahydrochloride (69.7% by weight based on the actual TETA content of the starting technical base) are obtained, which shows only a very weak spot of 1- (2'-aminoethyl-aminoethyl) piperazine in thin layer chromatography.

Example 2

To the mixture 250 ml conc. hydrochloric acid and 250 ml of water are added dropwise, with stirring and cooling, over a period of 30 minutes, 200 g of technical base containing 73.3 wt. AUNT. 1000 ml was then added to the solution. conc. hydrochloric acid and after heating to 50-55 ° C, 1000 ml of methanol preheated to 50-55 ° C are added in one portion with vigorous stirring. The precipitated white precipitate slurry was stirred further to cool to room temperature and crystallization was completed by standing overnight in a refrigerator at 5 ° C. The product was filtered off with suction and washed successively with 400 ml of conc. hydrochloric acid with methanol (1: 1), a mixture of 550 mL of methanol and 50 mL of conc. hydrochloric acid and 2 x 300 ml methanol. Drying in vacuo at 60 ° C afforded 290.7 g of crude TETA tetrahydro chloride, which was recrystallized as follows: the above amount of the automobile product was dissolved in 1400 mL of water, and the solution was filtered. 7000 ml of methanol preheated to 50-55 ° C are added simultaneously to the filtrate heated to 60 ° C with vigorous stirring. The precipitated product is filtered off with suction, washed with methanol (2.times.300 ml) and dried in vacuo at 60 DEG-70 DEG.

197 093

Example 3

200.0 g of tetrahydro chloride TETA, prepared according to example 2, are suspended in 4000 ml of anhydrous ethanol and the suspension is heated to boiling with stirring. Sodium ethanolate solution, prepared by dissolving 32.2 g of the salt in 625, is added to the boiling suspension. ml of anhydrous ethanol. The suspension is refluxed for a further 45 minutes after the addition of the ethanolate under vigorous stirring. The precipitated sodium chloride is then filtered off and the filtrate is allowed to cool to room temperature with stirring, whereupon TETA dihydrochloride crystallizes out. 121.2 g of pure TETA dihydrochloride are obtained, i.e. 80.7% of theory based on the tetrahydro chloride starting material and 59.0% of theory based on the actual TETA content of the starting base.

Example 4

14.6 g of pure tetrahydro chloride TETA, prepared according to Examples 1 or 2, are dissolved in 50 ml of water and the solution is run through a 20 mm diameter column packed with 130 ml of anion exchange resin in a 0H-loop (Zerollt PP) at 2 ml / min. and the column is then washed with the same flow rate through 150 ml of water. 211 ml of a solution containing 6.94 g of TETA base (i.e., 94.8% of theory) and 3.29 g of Cl are obtained. To this solution was added 0.60 g of tetrahydro chloride TETA and after dissolution, the solution was evaporated to dryness on a rotary evaporator. 12.3 g of an oily residue are obtained, which is dissolved by boiling in 300 ml of ethanol containing 0.1 wt. water. The solution is filtered and crystallized for 12 hours at -12 ° C. The precipitated product is filtered off with suction, washed with ethanol and dried under vacuum at 40 ° C. 9.62 g (84.3% of theory) of pure TETA dihydrochloride are obtained.

Example 5

29.5 of pure tetrahydro chloride TETA is suspended in 200 ml of methanol and a solution of sodium methoxide prepared by dissolving 5.0 g of sodium in 100 ml of methanol is added. After another 30 min. After stirring at 20 DEG C., the precipitated sodium chloride is filtered off with suction and the filtrate is evaporated to dryness in vacuo. The resulting oily yellow residue (26.0 g) was dissolved in anhydrous ethanol (700 ml), filtered and crystallized at -10 to 0 ° C for 16 hours. The precipitated product was filtered off with suction, washed with ethanol and dried at 40 ° C under vacuum. 19.78 g (90.2% of theory) of pure TETA dihydrochloride are obtained.

Example 6

A suspension of 29.2 g of pure tetrahydro chloride TETA in 500 ml of anhydrous ethanol is heated to boiling with stirring, and 112 ml of ethanol-alcohols sodium hydroxide containing a total of 8.0 g of this hydroxide are added to the boiling suspension. After 30 min. By boiling with stirring, the precipitated sodium chloride is filtered off and the filtrate is left under stirring to room temperature. The crystalline is completed by standing for 4 hours in the freezer, the product is filtered off with suction, washed with ethanol and dried. 16.62 G (75.8% of theory) of pure TETA dihydrochloride are obtained.

Example 7

To a solution of 15.97 g of henzaldehyde in 100 ml of gasoline was added dropwise with stirring over 10 minutes

197

7.31 g technical base with 73.3 wt. AUNT. The emulsion is heated to boiling, the gasoline solution is separated from a small amount of a tan oil, filtered while hot, and allowed to cool to room temperature after seeding with crystalline Sohiff base. The crystallization was completed by standing for 5 hours at -10 ° C. The product was filtered off with suction, washed with spirited petrol and air-dried. 12.9 Schiff bases are obtained, i.e. 85.7% of theory, based on the actual TETA content of the starting technical basis.

Example 8

To 50 ml of concentrated hydrochloric acid heated to 80 ° C was added, with stirring, 6 g of Schiff base from Example 7. The crystals precipitated from the lower aqueous phase were sucked off after 5 hours at + 5 ° C, washed three times with 20 ml of methanol each. dried in vacuo. 3.52 g of TETA tetrahydrochloride, suitable for the preparation of pure TETA dihydrochloride according to the examples, are obtained

3,4,5 or 6.

Example 9

The Schiff base (6.0 g) prepared according to Example 7 was dissolved by heating to 50 ° C in 50 ml of methanol, and 10 ml of conc. hydrochloric acid. Crystallization of the precipitated TETA tetrahydrochloride is completed by standing for 5 hours in a refrigerator at -12 ° C. The product is filtered off with suction, washed with methanol and dried under vacuum at 70 ° 0. 3.4 g (79.6% of theory of pure TETA tetrahydrochloride) are obtained.

Claims (2)

OBJECT OF THE INVENTION Process for preparing pure triethylenetetramine dihydrochloride from a technical product containing 60 to 80 wt. triethylenetetramine base, characterized in that the starting technical product is first neutralized with 15 to 20% hydrochloric acid, then the addition of concentrated hydrochloric acid in an amount of 6 to 24 wt. parts related to 1 wt. part of the starting technical product, precipitating crystalline triethylenetetramine tetrahydrochloride, which is isolated and from which it is removed after possible recrystallization 2 moles of hydrogen chloride by treatment with a base reagent, preferably an alkali metal hydroxide or alcoholate or an anion exchange resin in the OH-loop.