CS204904B1 - Method of producing n,n-dibenzylethylene-diamine salt of oxacillin - Google Patents

Description

The invention relates to a process for the preparation of the Ν, Ν'-dibenzylethylenediamine salt of oxacillin, i.e. 5-methyl-3-phenylisoxazole-4-carbaxylic acid, a known and clinically used semi-synthetic antibiotic. Said salt has a prolonged action (Antibiotics (Moscow (10) (6), 492 (1965)) as compared to the commonly used sodium oxacillin salt, and another advantage is its low solubility in water, which makes it possible to form suspension dosage forms.

The prior art process for the preparation of oxacillin Ν, Ν'-dibenzylethylenedlamine salt was to separately prepare an aqueous solution of oxacillin sodium salt and N, N'-dibenzylethylenediamine (hereinafter benzathine) sodium salt while adding the benzathine solution to the oxacillin solution with stirring. This formed a voluminous precipitate, difficult to filter, which was air-dried after washing with water. As a rule, the substance obtained had to be further purified by dissolving it in acetone, filtering the obtained solution and adding water again (U.S. Pat. No. 2,996,501). The disadvantage of this process is the fact that it produces a substance which can be isolated with great difficulty by filtration and whose drying takes up to 14 days to an unbearable time.

Surprisingly, it has now been found that a high-quality substance of the N, N'-dibenzylethylenedlamine salt of oxacillin, which does not need to be purified, with crystals so large that its easy isolation by filtration or centrifugation is quick and easy. sodium, with a soluble salt of N, N'-dibenzylethylenediamine, for example

204 904

204 904 in the aqueous medium according to the invention, characterized in that the reaction is carried out in a mixture of water with a water-miscible organic solvent, in particular a C 1 -C 3 alkanol, preferably ethanol, or β-dioxane, in a volume ratio of 1 t 2 to 4: 1, 8 preferably 2: 1, at a temperature of 0 to 25 ° C, and preferably 2 to 5 ° C, wherein the aqueous solution of ω, Ν'-dibenzylethylenediamine double-ethane is added to the reaction mixture at mole in the range of 30 to 120 minutes, preferably 80 to 100 minutes.

Suitably, this reaction is carried out by simultaneously adding an aqueous solution of Ν, Ν'-dibenzylethylenediamine, dipotanate and an aqueous solution of oxacillin sodium to a mixture of water and a water-miscible organic solvent.

The basic condition for obtaining the desired effect according to the invention, i.e. to produce a pure substance in crystalline form which is easy to filter and to dry more rapidly, is a gradual mixing of the solutions of both reactants, one to the other, preferably benzathine solutions to oxacillin or both. into a mixture of water with an alkanol of 1 to 3 carbon atoms. The sophisticated combination of the two solutions does not guarantee the formation of the final product crystals with the desired properties.

The reaction may be carried out at room temperature, i.e. between 15 and 25 ° C, but lower temperatures are more preferred; particularly preferred is the range of 2 to 10 ° C where the decomposition of the substance formed is substantially reduced.

It is also expedient to accelerate the drying if the precipitate formed is washed first with water, after filtration of the mother liquors, then with a C1 -C3 water-alkanol mixture and finally with a C1 -C3 alkanol itself or with diethyl ether.

The method according to the invention contributes substantially to improving the technology of an important form of clinically used drug and also to improving the quality of the active substance.

The following examples illustrate the process according to the invention but do not limit it in any way.

Example 1

Dissolve 100 g of benzathine dipotassium and 2 g of 245 g (1 equivalent) of exaoiline in 2 liters of distilled water. After filtration, the two solutions are slowly added dropwise to a mixture of 1200 ml of ethanol and 600 ml of distilled water over about 40 minutes while stirring. The resulting suspension is allowed to rest for 1 hour, then sucked off with a glass filter, washed twice 250 ml water, 2 x 200 ml ethanol and 100 ml diethyl ether. After drying at 45 DEG C. for 3 days, 297 g (96.4% of theory) of the product crystallized as the tetrahydrate are obtained. Active substance content 98.0% (on anhydrous substance), breakdown products content 1.3% Water content 7.1% ·

Example 2

2.45 kg of oral are dissolved in a mixture of 15 liters of water and 15 liters of ethanol with stirring

204 904 oxaoiline with an active ingredient content of 95.2% »1.0 kg of benzathine is dissolved in 20 liters of water with stirring. After filtration of both solutions, the benzathine solution is added slowly, with stirring, to the oxaoiline solution over about 90 minutes. Shortly after completion of the addition, a white precipitate is formed which gradually thickens. After standing for 45 minutes, it is filtered off, washed with a mixture of 2 liters of water and 2 liters of ethanol, then 3 liters of ethanol and finally 2 liters of diethyl ether. Dry in a box oven at 45 ° C for 3 days. 2.80 kg (90.8% of theory) of β are obtained with an active substance content of 96.7% and a breakdown content of 2.6% (based on the anhydrous substance).

Example 3

The procedure was the same as in Example 1 except that the temperature of the reaction medium was lowered to 5 ° C. Yield 286 g of product with an active ingredient content of 99.1% and a degradation content of 0.7% (based on the anhydrous substance).

Example 4

Solutions of 5 g of benzathine dipotassium in 100 ml of water and 12.29 g of oxaoiline sodium in 100 ml of water are added dropwise at a rate of 1 drop per second to a mixture of 60 ml of isopropyl alcohol and 30 ml of water. The suspension was allowed to stand for 1 hour, then filtered and washed with water (2 x 15 ml), ethanol (2 x 10 ml) and diethyl ether (5 ml). Dry in vacuo at 60 ° C for 3 days. Yield 14.5 g of product, containing 98.1% active ingredient and 1.2% decomposition products (anhydrous).

Claims (2)

A process for the preparation of an oxaoiline Η, Ν'-dibenzylethylenediamine salt by reacting an oxaoiline salt with an alkali metal, in particular a sodium salt, with a soluble salt of N, R * -dibenzylethylenediamine, e.g. mixtures of water with a water-miscible organic solvent, in particular a C 1 -C 3 alkanol, preferably ethanol or dioxane, in a volume ratio of 1x2 to 4: 1, preferably 2: 1, at 0 to 25 ° C Preferably, the aqueous solution of β, β'-dibenzylethylenedlamine dipotane is added to the reaction mixture at a rate of 1 mole within the range of 30 to 120 minutes, preferably 80 to 100 minutes. 204 904 2. A process according to claim 1, wherein the reaction is carried out with the simultaneous addition of an aqueous solution of ω, ib'-dibenzylethylenedlamine double salt and an aqueous solution of axacillin sodium to a mixture of water with a water-miscible organic solvent.