DE1080559B - Process for the production of sparingly water-soluble calcium salts of acid-stable penicillins - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of sparingly water-soluble calcium salts which are more acid-stable Penicillins with the exception of phenoxymethylpenicillin.

It has been found that the calcium salts of certain acid-stable, biosynthetic penicillins, such as p-cresoxymethylpenicillin, phenoxymethylpenicillins halogenated in the p-position, e.g. B. p-Chlorphenoxymethylpenicillin and PhenyhnercaptomethylpeniciUin, are sparingly soluble in water, ie, having a solubility of unf it 1%, in particular less than 0.4%, having at 24 ⁰ C.

The general formula of these acid stable biosynthetic penicillins is

C ₈ H ₁₀ O ₃ -NS-NH-CO-CH ₂ -A-

where A in the case of cresoxymethylpenicülins or p-chlorophenoxymethylpenicühns an oxygen and im In the case of phenylmercaptomethylpenicillin a sulfur atom and X a halogen atom or an alkyl group or, in case A has the meaning of a sulfur atom, a Means hydrogen atom.

In the production of the above acid-stable penicillins, so-called "precursors" cresoxyacetic acid, p-chlorophenoxyacetic acid or phenylmercaptoacetic acid is used. In the isolation and pure display Of the above-mentioned penicillins, these "precursor acids" always appear as an impurity Penicillins very similar distribution coefficients and dissociation constants very difficult from the penicillins can be separated. It has now been shown that the calcium salts of these penicillins are much heavier are water-soluble than the calcium salts of the "precursor acids", so that they can easily be prepared in pure form in this way the penicillins can be done.

The following are the solubility ratios of the calcium salts of some of these penicillins and their corresponding ones "Precursor acids" listed:

solubility substance g / 100 ml H ₂ O at 24? C. p-CresoxymethylpeniciUin Ca salt 0.128 p-cresoxyacetic acid Ca salt 0.522 Phenylmercaptomethylpenicillin Ca salt 0.388 Phenylmercaptoacetic acid Ca salt 2.796 p-Cl-PhenoxymethylpenicilHn-Ca-Salt ... 0.092 p-Cl-phenoxyacetic acid Ca salt 3 to 4

Method of manufacture

of sparingly soluble in water

Calcium salts of acid-stable penicillins

Applicant:
"BIOCHEMISTRY"

Company with limited liability,
Kundl, Tyrol (Austria)

Representative: H. Knoblauch, lawyer,
Leverkusen-Bayexwerk

Claimed priority:
Austria from. July 31, 1956

Dr. Hans Margreiter, Radfeld (Austria),
has been named as the inventor

To carry out the process according to the invention you can, for. B. a water-soluble salt of penicillins react with calcium chloride in aqueous solution, with at least 1 mol per 2 mol of alkali salt of penicillin Calcium chloride is applied; the application of an excess of calcium chloride is complete Precipitation of the calcium penile is advantageous. But you can also from the organic solvent phase bring salts of PenicilHne prepared according to the invention to precipitate. For example, a solution of the penicillic acid in question in butane oil, an aqueous solution of calcium chloride containing an equivalent amount containing calcium ions. The water content is then determined by azeotropic distillation removed, whereby the corresponding calcium penicillin then crystallizes out. Furthermore, for example a solution of the penicillic acid in question in butyl acetate be mixed with an anhydrous solution of calcium acetate in butane oil, whereby the Calcium salt of the penicüHns in question is excreted.

Here, too, it is advantageous to work with a small excess of calcium acetate.

In the following, some exemplary embodiments for the pure representation of such penile hnees will now be made use of the above differences in solubility.

example 1

6 g of p-cresoxymethylpenicilHn chew with one activity of 1208 JE / mg (iodometric test) are dissolved in 250 ml of water; 1.4 g are added to this solution Calcium chloride (anhydrous) dissolved in 60 ml of water is added. A well-crystallized one quickly separates Precipitation of calcium-p-cresoxymethylpenicilHn from.

009 507 / 40Ϊ

The precipitated crystallized compound is isolated after standing for several hours and washed with water and dried.

Yield: 4.5 g of calcium p-cresoxymethylpenicillin with an activity of 1470 JE / mg (iodometric test) corresponding to 91.3% of theory. Solubility: 0.128 g in 100 ml of water at 24 ° C. Water content of the crystallized substance: 4.50 ° / ₀ .

Example 2

4.23 g of p-chlorophenoxymethylpenicfflm potassium with an activity of 980 JE / mg (iodometric test) are dissolved in 150 ml of water; become this solution 0.7 g calcium chloride (anhydrous), which is dissolved in 70 ml water, is given. The resulting precipitate is isolated and dried.

Yield: 2.8 g of calcium p-chlorophenoxymethylpenicillin with an activity of 1400 JE / mg (iodometric test) corresponding to 94.6% of theory. Water content of Substance: 4.0%. Solubility: 0.092 g / 100 ml water at 24 ° C.

Example 3

6.5 g phenyhnercaptomethylpenicillin potassium with an activity of 1116 JE / mg (iodometric test) are dissolved in 50 ml of water and treated with a solution of 1.7 g calcium acetate (anhydrous) are added to 60 ml water. After the mixture has stood for a short time, it crystallizes Calcium salt of Phenyhnercaptomethylpenicillin in rosette form. The precipitate is after several hours Stand isolated in the refrigerator, washed with a little cold water and dried.

Elaboration: 4.2 g Calcmmphenylmercaptomethylpenicillin with an activity of 1480 JE / mg (iodometric test) corresponding to 86.0% of theory. Water content of the substance: 4.52%. Solubility: 0.388 g / 100 ml water at 24 ° C.

Example 4

5 g of p-cresoxymethylpenicillic acid with an activity of 1420 JE / mg (iodometric test) [theoretical value = 1634 JE / mg] are dissolved in 200 ml of butanol. 30 ml of an aqueous solution containing 1.12 g of calcium acetate (anhydrous) are added to this solution. The water content is removed by azeotropic distillation at 2 mm pressure, with the remaining Butanol solution crystallizes the calcium salt of p-cresoxymethylpenicillin. The precipitate is filtered off with suction and slurried in 250 ml of water at 24 ° C for further cleaning, then the calcium salt isolated and dried.

Yield: 4.11 g with an activity of 1450 JE / mg (iodometric test) corresponding to 84.0% of theory. Water content of the substance: 4.50%. Solubility: 0.128 g / 100 ml water at 24 ° C.

The alkaline earth metal salts prepared by this process can now be converted into their free in a manner known per se Acids or converted into the water-soluble alkali salts or into salts of organic bases.

The calcium salts of these penicillins are due

ίο their low water solubility also particularly good as Depot preparations suitable for injection therapy. You can z. B. with these salts with only one Injection of about 300,000 JE achieve a depot effect, similar to that of procaine penicillin, but with there is still the great advantage that instead of the procaine base, which often causes allergies, this is physiological valuable calcium ion is used. These salts are also suitable for oral therapy. Under the influence In the stomach acid, the free penicillic acids are formed from the salts, as a result of their acid stability stay fully active. In the duodenum, the precipitated penicillic acids are then converted into the easily water-soluble ones Converted to alkali salts; as a result of the resulting solution, these penicillin alkali salts are rapidly absorbed a.

It has also been shown that the calcium salts mentioned are practically as acid-stable as the crystallized ones, free penicillic acids, while the water-soluble alkali salts of the same acids have a lower level Have acid stability.

Claims (1)

Claim: Process for the preparation of calcium salts of acid-stable penicillins, which are sparingly soluble in water, characterized in that acid-stable penicillins of the general formula are used C ₈ H ₁₀ O ₃ - NS -NH-CO-CH ₂ -A- <f where A is an oxygen or sulfur atom and X is a halogen atom or an alkyl group or, in the case of A has the meaning of a sulfur atom, means a hydrogen atom, in the form of their free acids or their water-soluble salts in an aqueous medium with calcium ions to implement. Considered publications:
German Auslegeschrift No. 1 033 664;
"Österreichische Chemikerzeitung", Vol. 55 (1954), p. 16. © 009 507 / ΉΒ 4.60