CS240385B1

CS240385B1 - A method of purifying cephalotin salts

Info

Publication number: CS240385B1
Application number: CS846587A
Authority: CS
Inventors: Miroslav Veverka; Maria Tegzova
Original assignee: Miroslav Veverka; Maria Tegzova
Priority date: 1984-08-31
Filing date: 1984-08-31
Publication date: 1986-02-13
Also published as: CS658784A1

Abstract

Čistenie solí cefalotínu vo vodných roztokoch extrakciou pri kontrolovanom pH na zabezpečenie vysokej čistoty solí cefalotínu, substancie pre výrobu injekčnej formy antibiotika. Z vodných roztokov sa selektívne extrahujú nečistoty organickým rozpúšťadlom a roztok sa spracuje zrážaním alebo vysolením.Purification of cephalothin salts in aqueous solutions by extraction at controlled pH to ensure high purity of cephalothin salts, a substance for the production of an injectable form of the antibiotic. Impurities are selectively extracted from aqueous solutions with an organic solvent and the solution is treated by precipitation or salting out.

Description

24038S

BACKGROUND OF THE INVENTION The present invention relates to a process for the purification of the salts of the cephalotin antibiotic antibiotic and to the simultaneous regeneration of the carboxylic acid used in the mixed anhydride. The intermediate impurities may contain imperfectly removed starting materials as well as decomposition products of the reactants.

Such ballasts accompanying the desired substance often only in very small concentrations are difficult to remove. Thereby, the quality of the intermediate or final substance is reduced. The purity of the intermediate and the final substance is evaluated according to the criteria constituting binding analytical values containing, for example, evaluation of impurity, occurrence of haze, etc. Failure to comply with some of the criteria leads to the need to purify the substance at the cost of reducing the yield or even eliminate it .

For example, in the production of cephalotin in the sub-section] of the application DOS 2 725 519, the end of the reaction of the intermediate acid is isolated after acidification of the reaction. by extraction with a suitable solvent and subsequent conversion to sodium salt. However, the intermediate obtained is often a rye colored with a small amount of decomposition substances which cannot be removed by absorption of the activated carbon in the preparation of the final sodium salt.

Similar to the method of the Netherlands Patent No. 6,506,820 consisting of acylating with 2-thienylacetyl chloride followed by coagulation of the sodium salt, the product is often colored (expressed as absorbance of a 10% solution in water in 1 cm of quartz). 400 nm) surplus 0.3. In British Patent No. 1,472,966, nonionic resins are used to control the cefazoline antibiotic contaminants in a controlled manner. pH. In the description of the invention, the possibility of pre-purifying the reaction mixture by extraction followed by selective adsorption of the impurities on the polymeric nonionic resins by column chromatography is shown.

However, the disadvantage of this patent document is the high consumption of resins for cleaning, the necessity to isolate the cephalosporin in the form of an acid and the need for relatively long handling of the aqueous solution during elution, which adversely affects the stability of the substance.

Cephalotin sodium salt can be obtained by a well-known lyophilization process, for example as disclosed in U.S. Patent No. 4,029,655. German Patent Application No. 2,164,399 discloses salting out a sodium salt from aqueous solutions using an alkali metal salt, but in the case of use the mixed anhydrous sodium salt precipitates a small amount of the acid used, and in addition, a product with unsatisfactory coloring is obtained which needs to be purified by crystallization or resin chromatography.

Obdobné čs. No. 225,196 discloses a method for isolating the aqueous solutions of cephalotin sodium to pH1-2, extracting cephalotin as an acid into an organic solvent followed by extraction into water by treatment with sodium acetate solution by precipitation or salting out. However, the disadvantage of the process is the subjection of the labile cephalotin to a strong acidic environment, high consumption of the extravasant. agents and the beneficial effects of the alkaline environment to which the cephalotin molecule is particularly sensitive to prolonged handling with an aqueous solution.

These disadvantages are eliminated by the method of purifying the cephalotin salt solutions of general formula I,

wherein M is sodium, potassium, ammonium or substituted ammonium cation of the type R @ 1 R @ 3 R @ 3 wherein R @ 1 R @ 2 R @ 3 is hydrogen, C1 -C6 alkyl and C3 -C6 cycloalkyl, 7-aminocephalosporanic acid salt of the active 2-thiophenoctanoic acid derivative as chloride or mixed anhydride, characterized in that it is extracted from the solutions of the ces- phallo- salt salts with an organic solvent immiscible with water, of the type of halogenated aliphatic hydrocarbons or carboxylic acid esters, of the organic impurity and the carboxylic acid used for acylation at a pH of the solution of 3.6 to 5.1, in a ratio of 0.1 to 1.5 parts by volume of the extender for 1 part by volume of the solution, followed by isolation of either the cephalotin salt or the cephalotin released from the purified salt and the carboxylic acid derivative the acid used for acylation from the extract.

According to the invention, when the reaction is carried out in an aqueous medium, the organic solvent is removed from the acylation reaction or by extraction or alternatively, if the reaction is carried out in an anhydrous medium, it is extracted with 240385 5 with an aqueous solution of a suitable salt or distilled water. It is possible to dissolve the reaction mass by adding an aqueous salt solution suitable for forming an aqueous solution of cephalotin salts.

For the purification of the cephalotin salt solution, a salt of cephalotin formed with an alkali metal such as sodium, potassium, ammonium and mono- to trialkyl-substituted ammonium may be used.

Suitable formulations are, in particular, alkali metal hydroxide, bicarbonate or organic acid salts having a pKa of less than 5, and for example acetates or alkylamines such as triethylamine, diisopropylamine. The amount of the compound used to form the solicephaline is chosen such that it is added to form a solution, using 0.8 to 1.5 moles to achieve this purpose. part of the monohydric acid salt to 1 mol. dlel cephalotin.

The concentration of the aqueous solution of the alltalic salt or amine used to prepare the cephalotin solution is selected from 5 to 60 percent by weight, preferably so as to work with a saturated salt solution. The pH of the aqueous solution is. it is adjusted to a value of 3.6 to 5.1 by the addition of a suitable acid or base. The aqueous solution is extracted with a water-immiscible organic solvent.

Suitable solvents include halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, 1-chlorobutane, trichloromethane, trichlorethylene, ketone compounds such as methyl isopropyl ketone, methyl isobutyl ketone, 3-pentanone, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate. or a hydrogenase of a compound such as 1-butanol, isobutanol, 1-pentanol.

The amount of the extracting agent used to achieve the effect of the invention is preferably chosen to be after the first extraction! the color of the aqueous solution remained below 0.3. In practice, this means using per volume of aqueous solution of 0.1 to 1.5 volumes of extractant. The resulting aqueous solution is added to the precipitate by addition of a non-toxic alkaline salt.

As the non-toxic alkaline salt, preferably sodium chloride or an alkali metal salt of an organic acid with a pKa.m of less than 5 liters can be used.

The non-toxic alkaline salt may be added in the form of a solution, preferably a 20% to 60% aqueous or aqueous-alcoholic solution, or directly in solid form.

The amount of non-toxic alkaline salt used to exclude the cephalotin salt is preferably from 0.5 to 88 parts by weight per part by weight. The cephalotin sodium salt precipitated is obtained by filtration or centrifugation.

The cephalotin salt can also be isolated from the aqueous solution by precipitation by addition of an organic, water-miscible solvent.

B

Suitable solvents may be aliphatic alcohols, for example ethanol, iso-propanol, or ketone compounds such as ethethone or methyl ethyl ketone. The amount of agent used to precipitate the salt is preferably selected such that less than 3% by weight of the solution is left in the solution. salts of cephalotin. In practice, this means using 1.5 to 10 parts by weight of reagent per 1 part by weight of an aqueous solution. From the renumbered cephalotin salt solutions, it is possible to release the cephalotin by acidification and to isolate the precipitated cephalotin in free form by gravitation or filtration by well-known methods. It has been found that the process of the invention can be combined with a combination of selective extraction at a controlled pH, to remove impurities efficiently and at the same time to regenerate the carboxylic acid used in the mixed anhydride, as well as with subsequent salting out or precipitation. higher purity cephalotin salt, and alternatively it is possible to isolate the alkaline phalpfalin according to the procedures in which it has been treated with an ammonium or substituted ammonium salt. This at the same time simplifies the isolation of cephalotin when industrial scale, high-quality and high-quality parameters are retained.

The process of the invention demonstrates the examples transferred without limiting them. EXAMPLE 1 To a solution of 0.43 g of 2-thio-acetic acid and 0.43 ml of triethylamine in 6.5 ml of acetone was added a solution of 0.37 ml of pivalic acid chloride in 1.5 ml of acetone at -10 DEG C. stirring, a solution of 7-aminocephalosporanic acid sodium salt and 0.25 g of sodium bicarbonate in 10 ml of acetone-water [1: 1] was added to the filtered solution. The reaction mixture was stirred at -10 ° C for one hour at room temperature.

The acetone is distilled off under vacuum and the pH of the solution is adjusted by addition of acetic acid 4. Add 5 ml of dichloromethane and stir for 15 min. After separation of the organic layer, 15 ml of isopropyl alcohol was added to the color solution. After standing at 5 ° C, the precipitated crystals are filtered and washed with methanol. 0.72 g of 7- (2-thienylacetamido jcephalosporanic acid, sodium salt, m.p. 204 DEG-206 DEG C. (decomposition) and 0.2 is obtained). The pH of the solution is adjusted to 4.5 and 5 ml of ethyl acetate are added, and after stirring for 15 minutes, the organic layer is separated.

Claims

240385 and 25 ml of iso-propanol are added with stirring. The precipitated sodium salt was washed with ethanol and dried. 1.65 g of 0.2% sodium cephalotin are obtained. EXAMPLE 3 A 5 mL aqueous solution of Example 1 was prepared, the pH of the solution was adjusted to 4.4 with hydrochloric acid, and the solution was extracted with 2 x 2.5 mL ethyl acetate. After separation of the organic layer, the aqueous solution is adjusted to pH 7.0 and sodium chloride is added to the milk solution. After standing for 30 minutes, the precipitated crystalline product was filtered off and washed with acetone. 0.68 g of sodium cephalotin is obtained by coloring 0.2. Example 4 To a solution of 0.43 g of 2-thiophenacetic acid and 0.43 ml of triethylamine in 6.5 ml of dichloromethane was added a solution of 0.37 ml of pivalic acid chloride in 1.5 ml of dichloromethane at -10 ° C. . After stirring for 30 minutes, a solution of triethylamine salt of 7-aminocephalosporanic acid prepared from 0.68 g of 7-aminocephalosporanic acid and 0.51 g of triethylamine in 10 ml of dichloromethane is added. The reaction mixture was stirred at -10 ° C for one hour and one hour at room temperature. The reaction mixture is stirred with 10 ml of saturated sodium bicarbonate solution. after stirring for 10 minutes, the pH of the solution was adjusted to 4.5. After separation of the organic layer, sodium chloride is added to the colorless solution to turbidity. After standing for 30 minutes, the precipitated crystalline product is filtered off and washed with acetone. 0.7 g of 7- (2-thienylacetamido jcephalosporanic acid sodium salt with mp 204-206 ° C (decomposition) and 0.2 is obtained. Example 5 10 ml of a saturated solution of hydro is added to the reaction mixture obtained in Example 4 above. After separation of the organic layer, the pH of the aqueous solution was adjusted to 4.5 and extracted with 5 ml of ethyl acetate, the aqueous solution was washed with 10 ml of acetate and the pH was adjusted to 2. Distillation of the ethyl acetate gave 0.52 g of 7- (2-thienylacetamido-cephalosporanic acid, which provides 0.6 g of 7- (2-thienylacetamido) -cephalosporane sodium salt with 0.15 g of sodium sodium acetate in 5 ml of methanol, mp 204-206 ° C) EXAMPLE 4 Dichloromethane is distilled off from the reaction mixture obtained in Example 4 and 5 ml of water are added, and 5 ml of ethyl acetate are added and the pH is adjusted to 4.5 K to the aqueous layer containing the triethylammonium salt of 7 - (2-thienylacetamido jcephalosporane) sodium acetate (0.15 g) and isopropanol (15 ml) were added, and after stirring for 30 minutes, the precipitated crystalline product was filtered off and washed with acetone. 0.54 g of 7- (2-thienyl-acetamidojcephalosporanic acid sodium salt with mp 202-205 ° C (decomposition) and 0.2 coloring are obtained. Example 7 To a solution of 5.4 g of 7-aminocephalosporanic acid and 7, 9 ml of diisopropylamine in 740 ml of dichloromethane are added at -10 DEG C. to a solution of 3.2 g of thienylacetyl chloride in 15 ml of dichloromethane, after stirring for one hour at room temperature, the dichloromethane is distilled off and the residue is dissolved in 120 ml of water. The aqueous layer is washed with 50 ml of ethyl acetate and the pH is adjusted to 2.1. The extracts of ethyl acetate are stained with charcoal to give cephalotin, which gives a salt of 0, 25. FILL OUT

A process for the purification of cephalotin salts of formula I

(I) COOM 240385 wherein M is sodium, potassium, ammonium or substituted ammonium cation of the type R 1 R 5 R 5 N + wherein R 1 R 2 R 3 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, prepared 7-aminocephalosporanic acid-reactive acid derivatives 2-thiophenoctane, such as a] chloride or mixed anhydride, characterized in that they are extracted from the solecalphaline solutions! with a water-immiscible organic solvent, a type of halogenated aliphatic hydrocarbon or carboxylic acid ester, an organic purity and a carboxylic acid using a mixed anhydride, at a pH of aqueous solution of 3.6 to 5.1, in a ratio of 0.1 to 1.5 volumes of the extractant per 1 volume of solution followed by isolation of the cephalotin or cephalotin released from the purified salt and carboxylic acid derivative used to acylate the extract.

2. Process according to claim 1, characterized in that dichloromethane or ethyl acetate are used as extraction agents. 10

3. Process according to items 1 and 2, characterized in that the isolation of the carboxylic acid from the extract is carried out by distilling off the organic solvent.

4. A method according to items 1 and 2, characterized in that the isolation of the cephalotin salts is carried out by isolation.

5. Process according to claim 4, characterized in that the salting-out is carried out by the addition of non-toxic alkali salts, in particular a sodium chloride or alkaline salt of an organic acid having a pKa of less than 5, in an amount of 0.5 to 8% by weight. parts per 1 part by weight of cephalotin salt.

6. A method according to items 1 and 2, characterized in that the isolation of cephalotin salts is by precipitation.

7. The process according to claim 6, wherein the precipitation is carried out by addition of a water-miscible organic solvent, preferably an aliphatic alcohol, to isopropanol in an amount of 1.5 to 10% by weight. parts per 1 wt. parts of cephalotin.