DE1031795B - Process for the preparation of a salt from penicillin and a piperazine base - Google Patents

Description

Process for the preparation of a salt from penicillin and a piperazine base The invention relates to a process for the preparation of the penicillin salt of 2,5-diphenylpiperazine, in veterinary medicine, in human therapy, in agriculture and in animal breeding can be used.

The salts that the penicillin forms with organic bases have increasingly gained in importance; so are the salts of benzhydrylamine, procaine, quinine or N, N'-dibenzyl-ethylenediamine are widely used.

It has been found that the penicillin forms a salt which is sparingly soluble in water with the 2,5-diphenylpiperazine. Because of this poor solubility, when the salt is used pharmacologically, an effective concentration of penicillin in the blood is maintained for a longer period of time, with no adverse side effects due to the very low toxicity of the salt. The low water solubility of the penicillin salt of 2,5-diphenylpiperazine according to the invention compared to other penicillin salts with prolonged activity (see table below) allows the use of minimal doses of the salt to achieve chemotherapeutically effective long-lasting penicillin levels in the blood, thereby avoiding adverse side effects in patients who are allergic to penicillin and further reducing the possibility of certain strains of bacteria becoming resistant to penicillin. Water solubility Penicillin salt of 9 / l Benzhydrylamine. . . . . . . . . . . . . . . . . . . . . 6.4 Procaine ............................. 4.5 Quinine .............................. 2.7 2,5-diphenylpiperazine ... . .... . . . . ... 0.35 A great advantage of the penicillin salt prepared according to the invention is that there is no group in the molecule which can cause hypersensitivity to the pharmacological use of the salt. It is known that, for example, the procaine salt of penicillin can cause severe damage due to an over-sensitivity of the organism to the p-amino group of the procaine molecule. This damage was examined in particular by Tzanck, Sidi and Dob.kevitch (cf. C. Albahary, Maladies Medicamenteuses, Masson, Paris 1953, p. 121).

The new salt can be prepared according to the invention by in aqueous or aqueous-organic medium, a solution of a 2,5-diphenylpiperazine salt in water or in a suitable, water-soluble organic solvent reacted with an aqueous solution of a penicillin salt. One preferably uses the acetate of 2,5-diphenylpiperazine and the triethylamine salt of penicillin, this double conversion being carried out in water and the salt by suction or by centrifugation, washed with water and dried. It goes without saying that these operations must be carried out under sterile conditions if one wants to manufacture a product that can be used for therapeutic purposes. One can vary with regard to solvents, reaction temperatures and times, furthermore replace the 2,5-diphenylpiperazine acetate with all other salts of this base, which have suitable solubilities, or the triethylamine salt of penicillin by a penicillin salt of an alkali or alkaline earth metal or an organic one Replace base, provided that the solubility of this salt doubles the conversion permitted.

Although it is generally preferable to use a salt of penicillin To use G, one can also use any other's salt for special needs Penicillins (F, X, K, V etc.) or a mixture of two or more of these salts to process. The new salt according to the invention can also be used for separation and purification of penicillin can be used in its production and isolation. There the 2,5-diphenylpiperazine binds 2 molecules of penicillin, shows the new salt -den Advantage of greatly increased effectiveness, which makes the always annoying administration great Makes quantities of product unnecessary.

`: The new 2,5-diphenylpiperazine salt of penicillin is becoming common in animal and human medicine administered by the parenteral route, in the form of a suspension in a suitable medium, such as distilled water, physiological salination, 20% propylene glycol or other commonly used aqueous diluents. One can also use an oil like arachis oil, sesame oil, cottonseed oil or other assimilable ones Use iriglycerides., Such suspensions are prepared in the usual way.

The new salt can also be in the form of tablets, coated tablets or granules Find application or on liquid or solid carriers, which his Can be added to animal feed or sprinkled on plants.

From US Pat. No. 2,558,014, the salt is made from penicillin and became known to the N, N'-dibenzylpiperazine. This salt is a Monopenicillinate, while a dipenicillinate according to the method according to the invention is obtained. Dipenicillinates allow the administration of a much larger one Amount of penicillin than is the case with a monopenicillinate of the same weight is.

The solubility of the monopenicillinate of N, N'-dibenzylpiperazine in water, as can be seen from the comparative tests below, is 0.20 / 0, while that of the dipenicillinate of 2,5-diphenylpiperazine is only 0.03%. A considerable superiority can be seen in the lower solubility, as this extends the duration of its action when it is administered.

The inventive reaction of penicillin with a strong base, such as that represented by 2,5-diphenylpiperazine, proceeds more rapidly and leads to better yields than is the case with the reaction of N, N'-dibenzylpiperazine with penicillin. The N, N'-dibenzylpiperazine namely has only a relatively weak basicity due to the three-fold substituted nitrogen atom. Test report 1. Production of the monopenicillinate of N, N'-dibenzylpiperazine a) in aqueous medium 10 g of pure penicillin sodium (bacteriologically determined content = 990%) are dissolved at 20 ° C. in 40 cm3 of fine distilled water. In addition, 5.25 g of the pure N, N'-dibenzylpiperazine hydrochloride are dissolved in 120 cm3 of water and the pH of this solution is brought to a value of 6 by adding sodium hydroxide solution. The solution is poured over the course of 15 minutes while stirring of penicillin sodium into that of N, N'-dibenzylpiperazine, left to stand for 20 hours at 20 ° C., filtered off with suction, washed three times with 5 cm3 of distilled water and dried in vacuo. 6.3 g of the penicillinate of N, N'-dibenzylpiperazine are obtained. Bacteriological content determination ... 1045 [, / mg Chemical content determination. . . . . . . . 1050 p @ / mg b) in an aqueous-organic medium Dissolve 10 g of pure penicillin sodium at 20 ° C. in 30 cm3 of distilled water. On the other hand, 5.25 g of NN'-dibenzylpiperazine hydrochloride are dissolved in a solvent mixture of 30 cm3 of dimethylformamide and 35 cm3 of water. 12 cm3 of sodium hydroxide solution are added to this solution. in order to bring the pH to 6.2 to 6.3, heat to 45'C and pour the solution of penicillin sodium.

You cool down slowly, leave it to stand in the refrigerator for one night, vacuum , washes three times with 5 cm3 of distilled water and, after drying, receives Vacuum 3.4 g of the penicillinate of N, N'-dibenzylpiperazine, which is completely identical with the product obtained according to a).

Bacteriological content determination ... 1040 # t / mg analysis calculated found C5OH58081'6S2 C'd4 @ 40 @ 4 '@ T @ S Dipenicillinate des monopenicillinate N, N'-dibenzylpiperazine. N, N'-dibenzylpiperazine C 64.210 / 0 68 0/0 67.90 /, 1-1 6,250 / 0 6,660 / 0 6,70 / ,. N 8.980 / 0 9300/0 930/0 S 6.850 / 0 5.3 0/0 5.80 / 0 0 13.680 / 0 10.6 0/0 1080/0 The salt obtained is therefore the monopenicillinate of N, N'-dibenzylpiperazine.

2. Comparison of the solubilities of the monopenicillinate of N, N'-dibenzylpiperazine and of the dipenicillinate of 2,5-diphenylpiperazine. 0.100 g of the salt to be investigated is stirred for 2 hours at 20 ° C. in 5 cm3 of distilled water, filtered and the filtrate is diluted five times and determines the content bacteriologically and chemically. Results a) Salt of N, N'-dibenzylpiperazine prepared according to 1, a) .- Bacteriological content determination .. 2310 t / cm3 Chemical content determination ....... 2370 p./cm3 corresponding to a solubility of 0.200 / 0.

b) Salt of N, N'-dibenzylpiperazine according to 1, b) Bacteriological content determination .. 1860 p, / cm3 Chemical content determination ....... 2000 # t / cm3 corresponding to a solubility of 0.16010.

c) The solubility of the salt of 2,5-diphenylpiperazine is 0.03 0/0.

The following example explains the invention: Example production of the penicillin salt of 2,5-diphenylpiperazine _ Add 1 g of 2,5-diphenylpiperazine, F. 195 to 196 ° C (block), in 100 cc of distilled water, add 0.55 cc of glacial acetic acid and heated on the water bath to 60 to 80 ° C until completely dissolved. Man filtered and allowed to cool to room temperature. The solution thus obtained is then with stirring to a solution of 4 g of triethylamine penicillate in 20 ccm of distilled Water added. It is cooled to 10 ° C. and the crystalline mass is filtered off with suction washed with distilled water. This is obtained after drying in vacuo on phosphoric acid 3.5 g of the dipenicillin salt of 2,5-diphenylpiperazine. F: 219 ° C (below Decomposition), [a] D = + 212 4- 2 ° (c = 10 / a, in dimethylformamide). The yield is 9401, The salt is in the form of colorless prismatic needles, which are in formamide, Dimethyl-.formamide, Methoxyäthanö1, and 0.35 per 1000 soluble in water, in acetone, Alcohol, chloroform, ether and other common organic Solvents are insoluble.

Analysis: C4 $ H640RNBS, molecular weight 907 Calculated C 63.6%, H 6.0%, N 9.2%, S 7.0%; Found C 63.4%, H 6.0%, N 9.0%, S 7.0%.

Claims (3)

PATENT CLAIMS: 1. Process for the preparation of a salt from penicillin and a piperazine base by reacting a salt of this base in water or in an aqueous organic or water-miscible organic solvent with the solution of a penicillin salt in water or in an organic solvent and isolating the deposited Salt in the usual way, characterized in that a 2,5-diphenylpiperazine salt is used as the salt of a piperazine base. 2. Process according to Claim 1, characterized in that the water-soluble 2,5-diphenylpiperazine salt the acetate is used. 3. The method according to claim 1, characterized in that that the salt of triethylamine is used as the water-soluble penicillin salt. References considered: U.S. Patent Nos. 2,547,640, 2,558,014.