CS201492B1 - Method of producing therapeutically usable salts of semi-synthetic penicillins - Google Patents

Description

The invention relates to a process for the preparation of therapeutically useful salts of the semisynthetic penicillins of formula (I)

CH _S

R · CO · MH · CH — CH G //

I | | CH ₃ (I), a co-N-CHGOOMe wherein R represents a 5-methyl-3-phenylisoxazolyl-4-group or a 5-methyl-3- (o-chlorophenyl) isoxazplyl-4-group and Me an alkali metal atom, in particular of sodium.

The semisynthetic penicillins, 6-aminopenicillanic acid derivatives, are substances of advantageous therapeutic properties. In particular, a number of important antibiotics having activity against peniaillin resistant microorganisms (e.g. oxacillin, cloxacillin, dicloxacillin and flucloxacillin) have been found and put into practice in the isoxazole derivatives group.

The method for producing these antibiotics is well known, in particular from the relevant patent literature. They are obtained mainly by acylation of the acid. Antibiotics, both for oral and parenteral administration, are used in the form of alkali metal salts, especially sodium salts. These can be prepared, for example, according to MS. No. 117115 by neutralizing a solution of the appropriate penicillanic acid in a mixture of a water-immiscible organic solvent with a water-miscible organic solvent, preferably a 1: 1 mixture of butyl acetate and acetone, to neutralize the sodium salt of an aliphatic carboxylic acid with 1 to 1 5 carbon atoms, in particular solid sodium acetate at a temperature of 15 to 25 ° C. This procedure requires that sodium acetate dissolve as quickly as possible and that subsequent filtration takes place before crystallization of the sodium salt of the antibiotic occurs, which, as one skilled in the art will readily understand, can be easily achieved, especially when pure raw materials are used, or when the antibiotic sodium is prepared for an extended period of time at the same workplace. In such a case, it happens that the sodium salt of the antibiotic crystallizes into unreacted and undissolved! sodium acetate before it can be removed, for example by filtration. The source of the problem is that, unlike potassium acetate, which provides up to 40% ethanolic solutions, the acetate is saline, both anhydrous and in the form of the trihydrate, very poorly soluble in the solvent. This disadvantage could not be eliminated even when working at higher temperatures. These problems are largely eliminated by the procedure according to MS. No. 143831, wherein an ethereal or benzene solution of the appropriate penicillanic acid is neutralized with sodium oetane trihydrate, dissolved first in a minimal amount of water and then diluted with ethanol. Thus, multi-component mixtures are used, and some components, such as ether and water, do not mix together, which greatly complicates operational use. Another desirable step would be to simplify the reaction mixture and ensure that the reactants are mixed in the form of solutions from which the antibiotic sodium salt will crystallize in good yield.

Such a solution, which overcomes the above disadvantages, has been found and is the object of the present invention - a process for the production of therapeutically useful salts of semi-synthetic penicillins, which is characterized in that the penicillanic acid of the formula II

RCO NH CH-CHC2; ' _T1

II CH _S (lij,

CO-N-OH COOH in which R denotes the same as in formula I, dissolved in a water-immiscible organic solvent or in a mixture of a water-immiscible organic solvent with a water-miscible organic solvent, neutralizes with a methanol solution of a 1 to 5 atom aliphatic acid % of the alkali metal carbonate, preferably sodium acetate, in the anhydrous or trihydrate form, whereupon the precipitated salt of the semisynthetic penicillin of formula I is isolated.

As water-immiscible solvents, aliphatic ethers, esters, ketones or aromatic hydrocarbons, preferably butyl acetate, and water-miscible solvents acetone may be used.

The above neutralization can be carried out at a temperature of from 10 ° C to the boiling point of the reaction mixture, preferably at a temperature of 15 to 25 ° C.

Replacing ethanol with methanol as the solvent of sodium oetane brings considerable advantages. Both anhydrous sodium acetate and its trihydrate are smoothly dissolved in methanol to stable solutions of the desired concentration, for example, 10% anhydrous sodium oetate solution and 40% or even more concentrated sodium oetate trihydrate solution can be easily prepared. The methanolic solution oetanu solution having a concentration of 40% or possibly even higher, corresponds to the optimum 40% solution oetanu potassium, which is used as neutralizing agent in the preparation of potassium salt of benzylpenicillin (penicillin G. It methanol include economically least expensive _(solvents, its properties The process according to the invention has a wide application in the field of semisynthetic compounds, in particular a relatively low boiling point, which provides a quantitative removal from the reaction product (gas chromatography control). penicillins of the general formula I.

The following examples illustrate but do not limit the invention.

Examples

Example 1

For the experiments according to the invention, 160 ml of dried butyl acetate solution was used, which according to titration contained 12 g of free oxacillinic acid. The solution was obtained after acylation of 6-aminopenicillanic acid with 5-methyl-3-phenylisoxazole-4-carboxylic acid chloride in aqueous acetone in the presence of sodium hydroxide, which provided a pH ranging from 8.5 to 6.0: i to 80 ml of the previous solution was added with stirring 6 ml of methanol solution containing 2.0 g of sodium oetane trihydrate. The oxacillin sodium crystallized immediately. After standing for 4 hours, the sodium salt was filtered off with suction, washed with 30 ml of acetone and 30 ml of petroleum ether and air-dried. 5.9 g of oxacillin sodium monohydrate, m.p. 190 DEG C. (with decomposition), with a content of 95%, were obtained.

b) To the remaining 80 ml of the previous solution was added 14 ml of methanol solution containing 1.2 g of anhydrous sodium oetate with stirring at room temperature. Crystallization. started a little later than in the first case; the same isolation procedure yielded 6.15 g of oxacillin sodium with a content of 97%.

Example 2

150 ml of a butyl acetate solution containing 6.9 g of free oxacillinic acid obtained after acylation of the silylated 6-aminopenicillanic acid derivative with 5-methyl-3-phenylisoxazole-4-carboxylic acid chloride in methylene chloride medium was divided into two halves:

a) To 75 ml of the solution was added 1.0 g of sodium oetane trihydrate as a 20% methanol solution. After isolation as in Example 1, 3.0 g of oxacillin sodium with 98% drug content were obtained;

(b) 7.2 ml of methanol solution containing 0.85 g of anhydrous sodium oetate are added to 75 ml of the same solution. After isolation as before, 2.6 g of oxacillin sodium with 94% active ingredient content were obtained.

Example 3

To 30 ml of a 1: 1 v / v mixture of butyl acetate and acetone containing 5.0 g of 5-methyl-3- (o-chlorophenyl) -4-isoxazolylpenicillinic acid free titration was added 1.0 g of oetane trihydrate with stirring sodium 20% methanol solution. After isolation, as in the previous cases, 4.5 g of 5-methyl-3- (o-chlorophenyl) -4-isoxazolylpenicillin sodium salt was obtained with satisfactory elemental analysis, m.p. 190 ° C (dec.), 98%.

Claims (2)

OBJECT OF THE INVENTION, 1. Process for the preparation of therapeutically useful salts of semisynthetic penicillins of the general formula I ch ₃ R · CO · NH · CH · GH čZ | · I J (Π, CO-N-GH-GOOMe in which R is 5-methyl-3-phenylisoxazolyl-4-group or 5-methyl-3- (o-chlorophenyl) isoxazolyl-4-group and Me is an alkali metal atom, in particular sodium, characterized in that the penicillanic acid of the general formula II RCO · NH · CH-CH I I CO-N, GH pCH, Wherein R denotes the same as in formula I, dissolved in a water-immiscible organic solvent or in a mixture of a water-immiscible organic solvent and a water-miscible organic solvent, neutralizes with a methanol solution of a C1-C5 aliphatic acid salt with an alkali metal, preferably sodium acetate, in the form of anhydrous or in the form of a t-hydrate, whereupon the separated semisynthetic penicillin salt of the formula I is isolated. 2. The method according to item! characterized in that aliphatic ethers, esters, ketones or aromatic hydrocarbons, preferably butyl acetate, are used as the water-immiscible solvent.