CS240385B1 - Cephaelotine salts cleaning method - Google Patents

Abstract

Purification of cephalotin salts in aqueous solutions extraction at controlled pH to ensuring high purity of cephalotin salts substances for the manufacture of an antibiotic injection form. They are selectively extracted from the aqueous solutions impurities with organic solvent a the solution is treated by precipitation or salting out.

Description

2

Purification of cephalotin salts in aqueous solutions by extraction at controlled pH to ensure high purity of cephalotin salts, a substance for the production of an injectable antibiotic form.

From aqueous solutions, impurities are selectively extracted with an organic solvent, and the solution is treated by precipitation or salting.

The invention relates to a process for the purification of salts of the semi-synthetic cephalotin antibiotic, as well as the simultaneous regeneration of the carboxylic acid used in the mixed anhydride. Accompanying impurities may contain incompletely removed starting materials as well as decomposition products of the reactants.

Such ballasts accompanying the desired substance often at very low concentrations are difficult to remove. This reduces the quality of the intermediate or even the final substance. The purity of the intermediate and final substance is evaluated according to criteria forming a binding analytical evaluation including, for example, color evaluation, turbidity, etc. Failure to comply with any of the criteria leads to the necessity of subjecting the cleaning operation to a substance at the cost of reducing the yield or even disposing of it

For example, in the preparation of cephalotin according to published application DE 2,725,519, after the reaction is completed, the acid intermediate is isolated after acidification of the reaction. of the mixture by extraction with a suitable solvent and subsequent conversion to the sodium salt. However, the intermediate product obtained is often rye colored with a small amount of decomposition products which cannot be removed by absorption on activated carbon in the preparation of the final sodium salt.

Similar to the process described in Dutch patent no. No. 6,506,820 consisting of acylation with 2-thienylacetyl chloride followed by precipitation of the sodium salt by precipitation gives a product which often has a color (expressed as absorbance of a 10% solution in water in a 1 cm quartz rock at 400 nm) above 0.3.

In British patent no. No. 1,472,966 non-ionic resins are used to remove impurities of the antibiotic cefazoline in a controlled manner. pH. The description of the invention also discloses the possibility of pre-purifying the reaction mixture by extraction followed by selective adsorption of impurities on polymeric non-ionic resins by column chromatography.

However, the disadvantages of this patent are the high consumption of resins for purification, the need to isolate cephalosporin in the acid form, and the need to handle the aqueous solution during elution for a relatively long time, which adversely affects the stability of the substance.

Cephalotin sodium salt can be obtained by a well-known lyophilization procedure, such as disclosed in U.S. Pat. No. 4,029,655. German patent application no. No. 2,164,399 discloses the salting out of the sodium salt from aqueous solutions using an alkali metal salt, but when mixed anhydride is used, the precipitated sodium salt occludes a small amount of the acid used and additionally yields a product of unsatisfactory coloring which needs to be purified by crystallization or chi / omatography on resins.

Similar MS. AO č. 225,196 discloses a method of isolation consisting in acidifying aqueous cephalotin sodium salts to pH 1-2, 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. The disadvantage of the process, however, is to subject the labile cephalotin to a strong acidic environment, to a large consumption of extraction agent, and to the cautious treatment of an alkaline environment to which the cephalotin molecule is particularly sensitive during long-term handling of the aqueous solution.

These disadvantages are overcome by the method of purification of the cephalotin salt solutions of formula I,

wherein M is sodium, potassium, ammonium or a substituted ammonium cation of the type R 1 R 2 R 3 in which R 1 R 2 R 3 is hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 6 carbon atoms prepared from salts of 7-aminocephalosporanoic acid and reactive 2- Thiophenacetic acid chloride or mixed anhydride, characterized in that extracts of cephalotin salt solutions are extracted with an organic solvent which is immiscible with water, a type of halogenated aliphatic hydrocarbon or carboxylic acid ester, organic impurities and the carboxylic acid used for acylation at a pH of 3.6 to 5.1 , in a ratio of 0.1 to 1.5 parts by volume of extracting agent to 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 used to acylate the extract.

The process according to the invention is carried out such that if 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, extracted with an aqueous solution of a suitable salt. meat by adding an aqueous salt solution suitable to form an aqueous ¹ cephalotin salt solution.

An alkali metal salt such as sodium, potassium, ammonium and mono- to trialkyl-substituted ammonium can be used to purify cephalotin salt solutions.

Suitable for their preparation are, in particular, solutions of alkali metal hydrides, bicarbonates or salts with organic acids having a pK a value of less than 5, such as acetates or alkylamines such as triethylamine, diisopropylamine. The amount of the compound used to form the cephalotin salt is chosen to add a solution to the cephalotin salt, and 0.8 to 0.8 is used to achieve this.

1.5 mol. % of monobasic acid salt per mol. cephalotin.

The concentration of the aqueous solution of the alkali salt or amine used to prepare the cephalotin solution is selected from 5 to 60 percent by weight, preferably to work with a saturated salt solution. The pH of the aqueous solution was. adjusts to 'value

3.6 to 5.1 by addition of a suitable acid or base. The aqueous solution is extracted with a water-immiscible organic solvent.

Suitable solvents include halogenated aliphatic hydrocarbons, for example dichloromethane, dichloroethane, 1-chlorobutane, trichloromethane, trichlorethylene, ketone compounds such as methylisopropyl ketone, methylisobutyl ketone, 3-pentanone, acid esters such as ethyl acetate, isopropyl acetate or hydroxy, isobutyl acetate, isobutyl acetate, isobutyl acetate, isobutanol, 1-pentanol.

The amount of the extracting agent used to obtain the effect of the invention is preferably chosen such that after the first extraction the color solution of the aqueous solution remains below 0.3. In practice, this means to use 0.1 to 1.5 volume parts of exhalating agent per volume of aqueous solution.

The resulting aqueous solution is added to precipitate by addition of a non-toxic alkali salt.

As the non-toxic alkaline salt, preferably sodium chloride or an alkaline salt of an organic acid having a pKa value may be used. less than 5. ¹

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 alkali salt used to precipitate the cephalotin salt is preferably from 0.5 to 88 parts by weight per part by weight. The precipitated sodium salt of cephalotin is obtained by filtration or centrifugation.

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

B

Suitable solvents include alcoholic alcohols, for example ethanol, isopropanol, or ketone compounds such as oleate or trimethylethyl ketone. The amount of agent used to precipitate the salt is preferably selected so that less than 3% by weight remains in the solution. salts of cephalothin.

In practice, this means using 1 part by weight of an aqueous solution of 1.5 to 10 parts by weight of the reagent.

From the purified cephalotin salt solutions, it is possible to liberate the cephalotin by acidification and isolate the recovered cephalotin in free form by filtration or filtration according to generally known methods. It has been found that by the process of the present invention, it is possible to combine selective extraction at controlled pH to effectively remove impurities while regenerating the carboxylic acid used in the mixed anhydride as well as subsequent salting or precipitation to obtain a higher purity cephalotin salt and alternatively it is possible to isolate the alkali salt of cephalin according to those processes where an ammonium or substituted ammonium salt is used.

This also simplifies the isolation of cephalotin salt on an industrial scale, while maintaining high product quality parameters.

The process of the present invention is illustrated by, but not limited to, the following examples.

Example 1

To a solution of 0.43 g of 2-thioeneacetic acid and 0.43 ml of triethylamines in 6.5 ml of acetone is added at -10 ° C a solution of 0.37 ml of paleic acid chloride in 1.5 ml of acetone. After stirring for 30 minutes, a solution of 7-aminocephalosporanoic 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 and at room temperature.

The acetone is distilled off in vacuo and the pH of the solution is adjusted to 4 by the addition of acetic acid. 5 ml of dichloromethane are added and the mixture is stirred for 15 min. After separation of the organic layer, 15 ml of isopropyl alcohol are added to the colorless solution. After overnight at 5 ^° C, the precipitated crystals are filtered off and washed with methanol.

0.72 g of 7- (2-thienylacetamido -cephalosporanic acid, sodium salt, m.p. 204 DEG-206 DEG C. (decomposition) and a color of 0.2 is obtained.

Example g 0.45 cephalotin sodium is dissolved in 7- ml. distilled water. The pH of the solution was adjusted to 4.5 and 5 ml of ethyl acetate was added. After stirring for 15 minutes, the organic layer was separated and 25 ml of isopropanol were added with stirring. The precipitated sodium salt was washed with methanol and dried.

1.65 g of cephalotin sodium having a color of 0.2 is obtained.

Example 3

5 ml of an aqueous solution according to Example 1 are prepared, the pH of the solution is adjusted to 4.4 by addition of hydrochloric acid, and the solution is extracted with 2 x 2.5 ml of ethyl acetate. After separation of the organic layer, the pH of the aqueous solution was adjusted to 7.0, and sodium chloride was added to the milk haze. After standing for 30 minutes, the precipitated crystalline product was filtered off and washed with acetone.

0.68 g of cephalotin sodium having a color of 0.2 is obtained.

Example 1 4

To a solution of 0.43 g of 2-thiopheneacetic acid and 0.43 ml of triethylamine in 6.5 ml of dichloromethane is added at -10 ° C a solution of 0.37 ml of pivalic acid chloride in 1.5 ml of dichloromethane. After stirring for 30 minutes, a solution of triethylamine salt of 7-aminocephalosporanoic acid prepared from 0.68 g of 7-aminocephalosporanoic acid and 0.51 g of triethylamine in 10 ml of dichloromethane is added. The reaction mixture was stirred at -10 ° C for 1 hour and 1 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 until turbid. After standing for 30 minutes, the precipitated crystalline product is filtered off and washed with acetone.

0.7 g of 7- (2-thienylacetamido -cephalosporanoic acid, sodium salt, m.p. 204 DEG-206 DEG C. (decomposition) and a color of 0.2 is obtained.

Example 5

10 ml of saturated sodium bicarbonate solution are added to the reaction mixture obtained according to the example. After separation of the organic layer, the pH of the aqueous solution is adjusted to 4.5 and extracted with 5 ml of ethyl acetate. The aqueous solution was overlaid with 10 ml of acetate and the pH was adjusted to pH 5

2. Distillation of ethyl acetate yields 0.52 g of 7- (2-thienylacetamidoycephalosporanoic acid) which, by adding 0.15 g of sodium acetate in 5 ml of methanol, yields 0.6 g of 7- (2-thienylacetamido-iodophosphoric acid sodium salt, mp 204-206 ° C). C (decomposition) and color 0.15.

example

The dichloromethane is distilled off from the reaction mixture obtained according to the example, and ml of water and 5 ml of ethyl acetate are added and the pH is adjusted to 4.5. 0.15 g of sodium acetate and 15 ml of isopropanol were added to the aqueous layer containing the triethylammonium salt of 7- (2-thienylacetamido -cephalosporanoic acid), and after stirring for 30 minutes, the precipitated crystalline product was filtered off and washed with acetone.

0.54 g of 7- (2-thienylacetamido) -cephalosporane sodium salt, m.p. 202 DEG-205 DEG C. (decomposition) and a color of 0.2, is obtained.

Example 7

To a solution of 5.4 g of 7-aminocephalosporanoic acid and 7.9 ml of diisopropylamine in 740 ml of dichloromethane is added a solution of 3.2 g of thienylacetyl chloride in 15 ml of dichloromethane at -10 ° 10. After stirring at room temperature for 1 hour, the dichloromethane was distilled off and the residue was dissolved in 120 ml of water. The reaction mixture was overlaid with 30 mL of ethyl acetate and adjusted to pH 4.2. The aqueous layer is again overlaid with 50 ml of ethyl acetate and the pH is adjusted to 2.1.

Ethyl acetate extracts are colored with activated carbon. Cephalotin is obtained, which gives a gray salt of 0.25 color.

Claims (7)

SUBJECT CLAIMS 1. A process for the purification of cephalotin salts of the formula I We claim: COOM (I) wherein M represents sodium, potassium, ammonium or a substituted ammonium cation of the type R 1 R 2 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 from 7-aminocephalosporanoic acid salts; . of a reactive 2-thiopheneacetic acid derivative as well as a chloride or mixed anhydride, characterized in that they are extracted from the cephalotin salt solutions. a water-immiscible organic solvent of the type halogenated aliphatic hydrocarbons or carboxylic acid esters, organic impurities and the carboxylic acid used in mixed anhydride, at an aqueous solution pH of 3.6 to 5.1, in a ratio of 0.1 to 1.5 parts by volume of the extracting agent per 1 part by volume of the solution followed by isolation of the cephalotin salt or cephalotin released from the purified salt and the carboxylic acid derivative used for acylation from the extract. 2. The process according to claim 1, wherein the extraction agents are dichloromethane or ethyl acetate. 3. The process according to claim 1, wherein the isolation of the carboxylic acid from the extract is carried out by distilling off the organic solvent. 4. A process as claimed in claim 1, wherein the isolation of cephalotin salts is carried out by salting out. 5. The process according to claim 4, wherein the salting-out is carried out by adding non-toxic alkaline salts, in particular sodium chloride or an organic acid alkaline salt having a pKa value of less than 5, in an amount of 0.5 to 8% by weight. parts per 1 wt. % of cephalothin salt. 6. The process according to claim 1, wherein the isolation of the cephalotin salts is effected by precipitation. 7. The process according to claim 6, wherein the precipitation is carried out by adding a water-miscible organic solvent, preferably an aliphatic alcohol, in particular isopropanol, in an amount of 1.5 to 10% by weight. parts per 1 wt. parts of cephalotin.