SU588920A3 - Method of preparing cephalosporin combinations - Google Patents

Description

where R has the indicated meanings

in anhydrous organic solvent at a temperature of 80-170 ° C in the presence of a heterogeneous catalyst — ion exchange resins, which are copolymers of divinylbenzene and styrene, which contain sulfo groups in the H-form or tertiary amino groups in the form of salts with acids.

A significant advantage is that the penicillin or cephalosporin molecule is statistically much less in direct contact with an acidic substance, since, in addition to the nearest neighborhood of the catalyst surface, it is in a neutral solvent environment.

This may affect the time required to terminate the process, but it prevents the side reaction of the decomposition of the fragile β-lactam bond, as well as reduces the degree of decarboxylation when using free penicillanic acid sulfoxide for the reaction. No less important are other advantages of using ionites as a catalyst, namely: ease of removal of the catalyst from the reaction medium by filtration, the possibility of repeated use of the same catalyst, as well as its regeneration while reducing its activity, selective sorption of some contaminants as a specific property of ionites, continuous reaction management.

For the reaction, readily available and cheap ion exchangers are used, which are widely used in ion exchange processes, are resistant to high temperatures, organic solvents, oxidizing agents, and are characterized by a degree of dissociation and structuring that are favorable for the course of the reaction.

The ionites used according to the invention include copolymers of styrene and divinylbenzene, containing an active acid residue such as sulfonic. To this type of catalysts belong, for example, Amberlite 1R-120, Dowex 30, Daux 50, Resex R, Zerolite 225, Levotite 5-100, Ionac C-240, Permutite XP, Permutite RS or their equivalents, for example, cationite SS. Strong or weakly basic anion exchangers are also used, for example, Amberlite 1 RA-400, Dowex-1, Dowex-2, Permutite ESB, in the form of salts with such strong inorganic acids as sulfuric or phosphoric, or organic acids, for example, alkanesulfonic acids, such as methanesulphonic acids., or arylsulphonic acids, for example p-toluenesulphonic acid. The amount required for the reaction of the catalyst is established experimentally, depending on its strength and exchange ability. Typically, the ion exchanger is used in an amount of at least 0.126 mg / eq per 1 mmol of nenicillin sulfooxide.

The reaction is carried out by heating the penicillin oxide sulfo in the free acid form of the ester, in an organic solvent that does not react with the substrates and products, or in an appropriate solvent mixture at temperatures ranging from 80-170 ° C, preferably at the boiling point of the solvent, most often within 100 - 130 ° C, which provides a relatively fast reaction without the need for mechanical mixing. Highly boiling esters of aliphatic acids, for example n-propyl, n-butyl, isobutyl, secondary butyl acetates, and high boiling ketones, such as methyl isobutyl ketone, methyl n-propyl ketone, ethyl butyl ketone, belong to FAVORABLE solvents and other high-boiling aliphatic ethers and diesters, for example dioxane, di-n-butyl ether, 1,2-dimethoxyethane, etc., such aromatic hydrocarbons as toluene, xylene, and also tertiary amides such as dimethylformam. and dimethylacetamide, or the corresponding mixtures of these solutions viewers.

According to the invention, the time required for the complete conversion of the substrate depends on the starting penicillin sulfoxide, the solvent used, the reaction temperature, and the ion exchanger, and ranges from 2 to 24 hours. Maintaining the process at a higher temperature shortens the reaction time, but causes the formation of a significant amount of by-products. It has been established that the conversion of the reaction of free acid sulfoxides proceeds several times faster than the reaction of the conversion of esters. The time required to finish the process is determined on the basis of thin layer chromatography. The reaction is considered complete when the chromatogram shows the complete or almost complete disappearance of the substrate.

For thin-layer chromatography, all of the following examples use Snalikel G according to Stahl as the carrier phase, and as developing mixture ethyl acetate-benzene in a ratio of 1: 3 (I) or n-butanol-ethanol-acetone-1 water in a ratio of 4: 1:: 4: 1 (II). For simplicity, the examples indicated only the numbers of these developing mixtures.

Chromatograms were shown by iodine-starch method.

Preparation of ion exchange catalysts.

The cation exchangers are converted into the acid form (P) by well-known methods, and then filtered and washed until the drain becomes neutral. The ion exchanger prepared in this way is weighed in distilled water and heated for one hour at a temperature of 80 ° C, then filtered, washed with water and acetone, and then dried in air for 24 hours. Anion exchangers are converted into alkaline form, and then the corresponding acid is precipitated on them, after

This is washed with water until the effluent is neutral, and then with acetone, and air dried for 24 hours.

Example 1. A mixture of 3.7 g (mmol) of phenoxymethylenicillin sulfoxide, 2 g of Zololite 225 (H) and 50 ml of dry, acetic acid-free isobutyl acetate, is heated in a round bottom flask equipped with an azeotropic dryer and reflux condenser at a temperature of boil for 2.5 to 3 hours. The end of the reaction is set on the basis of thin layer chromatography (mixture II). After completion of the reaction, the mixture is cooled to a temperature of 5 - 10 ° C and the ion exchanger is filtered off, which, after washing with ethyl acetate, acetone and water, and also after thorough preparation, is used for subsequent cephalosporin production reactions. The filtrate is washed with 25 ml of cold water and extracted with 3x25 ml of 0.5N. sodium bicarbonate. The combined carbonate extracts are washed twice with 20 ml of n-amyl alcohol, cooled to a temperature of 0 ° C., and the triledas are extracted with 30 ml of ethyl acetate at a pH of about 2.7. The combined acetate extracts are washed with a small amount of water and brine, dried over anhydrous sodium sulphate and evaporated to dryness. 2.2 g (63.5%) of a light yellow foam-like product contaminated with a small amount of degradation products such as a decarboxylated product was obtained. The precipitate is dissolved in about 4-5 ml of anhydrous ethanol and 1.2 ml of dibenzylamine is added. Crystallization of salts is initiated by performing a scratch on the vessel wall. After completion of crystallization, carried out for 18 hours at a temperature of about -5 ° C, the isolated crystals are filtered, washed with 3 ml of cold anhydrous ethanol and 5 ml of dry ethyl ether and dried to constant weight in a vacuum desiccator. 2.3 g of dibenzylamine salt of 7-phenoxy-acetamido-dodecetoxycephamcarboxylic-4 acid were obtained with a melting point of 136-138 ° C (with decomposition). Chromatographic analysis of the product revealed its uniformity. Spectral analysis in the infrared region shows the following main absorption bands: 3450, 1760, 1670, 1630, 1595, 1500, 1240, 1040, 910, 760, and 695 cm.

About 0.5 g of a decarboxylated product, also possessing a cephem system, was isolated from the isobutyl acetate solution remaining after extraction into carbonate of compounds with a carboxyl group.

Example 2. A mixture of 3.66 g (10 mmol) sulfonic acid penicillin V, 1 g Zerolite 225 (H) and 100 ml of methyl isobutyl ketone is heated under reflux in a nitrogen atmosphere for 2.5 hours. The progress of the reaction is observed with the aid of thin-layer chromatography (mixture I). The product is isolated according to the method described in Example 1, wherein

1.4 g (40.2%) of 7-phenoxy-acetamido-dodecetoxy-sporic acid are obtained in the form of a light yellow foamy precipitate. After dissolving in ethyl acetate, extracting in g of water at pH 7.5 and acidifying the aqueous phase and 5 and sulfuric acid to a pH value of about 2.7, a white amorphous precipitate is precipitated. The precipitated precipitate is filtered off, washed with water and dried over PaOs. After drying, the precipitate is dissolved in n-butanol, and a solution is obtained at a concentration of about 8% and a calculated amount of titrated β-butanol solution of sodium 2-ethylcapronate is added while immiscible. Received 1 g of sodium salt of 7-phenoxyacetamidodesacetocycephalosporic acid. The infrared spectrum reveals the existence of a band originating from the p-lactam moiety at 1750 cm for the free acid, and for the sodium salt at 1745 cm g

Froze A mixture of 1.8 g (6 mmol) of penicillin Sulfoxide V, 0.3 g of Zerolite 225 (P), 30 ml of isobutyl acetate, 20 ml of benzene and 1 ml of dimethyl acetamide are heated under reflux so that the condensate passes through the nozzle for an azeotropic essence. After 2.5 hours, it was determined that the original sulfoxane completely reacted. 11 rods are isolated by the method described in previous

0 examples. Obtain 0.8 g of crude 7-phenoxyacetamide dozacetoxy-D-cefemcarboxylic-4 acid (45%), purity 95.2%, which is converted into dibeizyl ammonium salt, and get 0.82 g salt with a temperature

Melting 5: 134 - 137 ° C (with splitting).

Example 4. The procedure is repeated as in Example 3, using instead of the nozzle for azeotropic drying of the Soxhlet apparatus filled with anhydrous calcium sulfate and magnesium sulfate. Obtain 0.9 g (51%) of 7 - phenoxyacetamido deacetoxy - D - cefemcarboxylic acid-4. After conversion to the dibenzylammonium salt, 1 g of product is obtained with a melting point of 132-135 ° C (with cleavage).

Example 5. The procedure is repeated as in Example 4, using Reex (H) + in the amount of 0.75 instead of Zololit 225. Obtain 0.75 g (42.52) of 7-phenoxyacetamido deacetoxy-D-cefemcarboxylic-4 acid and 0.4 product not containing carboxyl group. The melting point of the free acid is 167 - 17 HS (with decomposition).

Example 6. The procedure is repeated as in Example 4, using 225.05 g of Dowex 1 instead of Zololite, with methanesulfonic acid applied as described above. 0.95 g (53%) is obtained, with a purity of 94.6

raw

7-phenoxy-acetamidodedoxy-D-cefemcarboxylic-4 acid, which, after purification, reveals spectral conformity to the reference product. Melting point 165-168 ° C (with splitting).