DE2221046A1 - ANTIBIOTICS AND THE METHOD OF MANUFACTURING THEREOF - Google Patents

Description

Dr. F Zumstein son. - Dr. E. Assmann
Dr. R. Koenigst-rgc - ~ <\ _.-.!. Phys. R. Holsbauer 2221046

Potent advocates 8 monks 2, brewing horse · 4 / lli

53 / My
Case 456

SNAM PROGETTI SpA, Milan / Italy

Antibiotics and their method of manufacture

The invention relates to the enzymatic cleavage of natural Penicillins and the enzymatic synthesis of "sera-synthetic" penicillins with the action of insoluble ones Acilase and the enzymatic cleavage or synthesis of compounds that have similar therapeutic properties exhibit. The invention particularly relates to cleavage and synthesis processes, or in a different order Synthesis or enzymatic cleavage processes of certain antibiotics, especially those belonging to the class of include so-called "natural" penicillins. The term "natural" penicillins is intended to include penicillin compounds, obtained by fermentation with Penicillum chrisogenum in the presence of suitable precursors.

The invention also relates to those according to the invention Process obtained products, The present invention can be used, for example, 6-aminopenicillanic acid and this latter acid can

309846 / $ 117

for this purpose, new semisynthetic penicillins, which are stable to ß-lactamase, are used enzymatically are to be produced and which have a broader spectrum of activity.

The method according to the invention is also suitable for the cleavage or synthesis of compounds which are similar have therapeutic properties like penicillins. In the method according to the invention one uses a enzymatic preparation which is insoluble in fibers and which gives a remarkable improvement in Properties of the finished product is preserved. The procedures are also easy to perform, and that brings with it that the process costs and thus also the product costs are reduced.

6-Amino-penicillanic acid (which is found in of the present application is referred to as "6-APA" for the sake of simplicity) is a valuable starting material for the production of semi-synthetic penicillins. The production of 6-APA by using direct fermentation Penicillium chrysogenum is in the absence of precursors. technically very complex and the yields are very low. Recently, chemical processes have been proposed which are also relatively expensive and in which a special one Technology is required because of the instability of the raw materials and the finished products. In these procedures decomposition products are formed and this entails considerable losses.

In the enzymatic processes in use today, cells of suitable microorganisms are used which Penicillin acilase. Because these cells are used only once and are used in relatively high concentrations in order to shorten the hydrolysis times, the cells that contain the enzyme have to be continuously

309846/1175

can be restored again. Besides, the Extraction of the hydrolysis product, 6-APA, from the reaction mixture is very difficult and the resulting product must be crystallized several times and often contains protein material that, if not for example by enzymatic Digestion with proteolytic enzymes is removed, while the formation of the resulting penicillins is allergic Causes phenomena, i.e. causes adverse effects. Through all of this, prices are increased and the technology of the manufacturing process is very complex. The method according to the invention overcomes those described Disadvantages and shows significant advantages.

The enzymatic preparation, which is embedded in filamentous structures or filamentary structures, retains its Activity for very long times samples retained their activities for a long time in many work cycles, for example, unchanged over the course of 12 months. The extended activities of the structures of the invention bring many advantages. This greatly simplifies the process, making the catalyst cheap and besides, the price of the finished product is greatly reduced. The cost of the catalyst is in comparison insignificant in relation to the procedure. In the process according to the invention, a mixture is treated which is a Contains antibiotic, which belongs to the class of natural penicillins, with filament-like structures that create an enzymatic Embedded preparation included. The products obtained are then separated and, if necessary, in a known manner further processed into other penicillin derivatives.

The fibers that contain the enzyme are washed immediately after the spinning process to remove any impurities from the outside adsorbed on the fibers. After washing, the fibers are used in catalyzing the reaction

309846/1175

-4- 22210A6

and since the protein does not diffuse into the reaction mixture can, you get a. very pure product .. that is free of the protein impurities that are particularly important very much because of the allergy phenomena mentioned above

are dangerous. The catalyst, which is insoluble by the process according to the invention, can be used in the case of discontinuous Procedures are used. He is contacted with the reaction mixture, whereby the penicillin hydrolyzes, and when the hydrolysis is complete, the reaction mixture is separated from the catalyst and the catalyst is treated with fresh reaction mixture. Some of the catalysts can also be used in continuous processes, for example in a column. The solution of penicillin compounds that may be used is buffered, is passed through a column containing the enzymatic fibers. By setting appropriately The flow rate and the amount of fibers can be used to obtain a flowing mixture that is as strong as hydrolyzed possible, i.e. which has the highest possible degree of hydrolysis.

It is also known that the same enzyme is present in reaction media with an acidic pH acts as an acylating agent for 6-APA (6-APA aciler) and whereby one goes through enzymatic synthesis can synthesize new penicillins from reaction mixtures containing 6-APA and carboxylic acid or derivatives thereof.

The same device that is used for hydrolysis can also be used to produce semisynthetic penicillins synthesize by combining the insoluble enzyme with a mixture that contains 6-APA and the desired carboxylic acid, treated or by better reactive derivatives of the carboxylic acid such as amide or N-acyl derivatives of Glycine sets in.

309846/1175

The enzymatic catalyst is according to an insolubilization process, as described in Italian patent 836,462. According to the Processes of this patent specification can be used to produce fibers which contain embedded enzyme Polymer solutions used as the starting material, which result in fibers and in which enzymatic preparations in the form very small droplets on the order of emulsions are dispersed.

The emulsion obtained in this way can be spun wet or dry to obtain a fiber that has very small holes or cavities inside, in which enzymes are arranged, which are separated from their surroundings with a very thin membrane that prevents the enzyme escapes and disperses in the reaction mass, but this allows the enzyme to achieve its full catalytic effect Can make an impact. The polymers capable of embedding or enveloping enzymes should be mentioned Cellulosic, esterified polymers, nitrates, polyolefins, polymers and copolymers obtained from acrylonitrile, Acrylates, methacrylates, vinyl esters, vinyl chloride, vinylidene chloride, styrene, and also polyamides, Butyral polyvinyl and other similar products.

The enzymes that are embedded can come from crude extracts obtained from cells of fungi or actinomycetes (Aspergillus, Penicillium, Botrytis cinerea, Fusarium, Mucor, Alternaria, Streptomyces, etc.) and that are specific are suitable for the enzymatic cleavage of penicillin (α-phenoxymethylpenillin), or they can originate from cells of bacteria (E.coli, B.Megaterium, Aerobacter aerogenes, Alcaligenes faecalis etc.) that are specifically suitable for the enzymatic cleavage of penicillin G (benzylpenicillin). In the case of hydrolysis, if you want to produce 6-APA, it is possible to use aqueous

309846/1175

Use solutions of the penicillin salt used as starting material, using different concentrations between 1 and 6% w / v, preferably 2 to 3% w / v, used. The solution is kept at a pH around 8.0 by automatically adding alkali. Is working one continuously, so one can, to the tedious control of the pH value at different column heights bypass, if necessary use buffered penicillin solutions.

In the case of syntheses, one can possibly use a solution which contains 6-APA in 1 to 3 w / v% amounts and which contains the desired acid or a derivative, preferably an amine or N-acyl derivative of glycine . The pH value is automatically kept at around 6.0. Both the hydrolysis and the synthesis can be carried out at temperatures in the range between 15 ¹ ^ 60 ^° C., preferably at temperatures in the range from 37 to 40 ^° C.

In the process according to the invention, penicillins which can be hydrolyzed are those which have the following formula

R-C-NH-CH-CH "

Il I I

O CO-N CH - COOH

where R is an alkyl group with 1 to 10 carbon atoms, an alkenyl group with 3 to 10 carbon atoms, an aralkyl group, the group R ¹ OCHp- and the group R ¹ SCH ₂ - and where R ^{1 is} an alkyl, alkenyl, or Represents a phenyl group or a phenyl group monosubstituted with halogen, -NOp, alkyl, alkenyl or alkoxy groups.

309846/1175

Penicillins that can be used in syntheses can are selected from those of greater therapeutic importance and use such as, for example 6- (a-Phenoxypropionamido) -penicillin, 6- (oc-Phenoxybutyramido) -penicillin, 6- (2,6-Dimethoxybenzamido) -penicillin, 6- (S-methyl-J-phenyl- ^ isoxazolcarboxyamido) -penicillin, 6- (S-methyl-S-o-chlorophenyl ^ -isoxazolcarboxyamido) -penicillin, e-iDC-J-a-aminophenylacetamidoJ-penicillin etc.

As already stated, the method according to the invention can also advantageously be used for enzymatic cleavage and for Enzymatic synthesis of compounds can be used that have therapeutic properties that are similar are like those of the penicillins. In particular, when operating according to the aforementioned method, mold derivatives can be used or dissolve or split products obtained from mushrooms and manufacture semi-synthetic products that have therapeutic properties similar to penicillins and which at the same time do not cause allergic symptoms.

In this way, cephalosporin derivatives can be enzymatically cleaved or synthesized, which also have a wider range of applications exhibit.

The following examples illustrate the invention without, however, restricting it.

example 1

While stirring, 20 g of cellulose triacetate (Fluka) are dissolved in 280 g of methylene chloride (C.Erba) in a reactor. Separately, a solution of the enzyme is prepared: E. coli cells (60 g dry weight), which have been prepared by fermentation in a suitable medium in the presence of phenylacetic acid, are placed under ultrasonic vibration in a phosphate buffer (0.01 M, pH = 7.0 ) given. The crude solution thus obtained is treated for 3 minutes at 50 ⁰ C.

309846/1175

~ ⁸ ~ 22210A6

and then precipitated with ammonium sulfate at pH 5.5, isolating the fraction with 25 to 75% saturation.

This last fraction is dissolved in 30 ml of phosphate buffer (0.01 M, pH = 8.0) containing 30% (vol / vol) glycerol. The enzymatic solution thus obtained is added to the polymer solution, the emulsion of the two phases is achieved by vigorous stirring at ⁰ ° C. for 30 minutes. The emulsion is then placed into a small spin vessel which is maintained at -6 ⁰ C, and then spun under Np-pressure. Toluene is used at room temperature, in which the thread coagulates, which is then wound up on a distaff. To remove the toluene, it is dried in vacuo for a few hours.

37 g of the fiber thus obtained are placed in a glass column which has a jacket and is 70 cm high and has a diameter of 3 cm. The column is washed with water and glycerol until no more protein can be detected in the wash water. 600 ml of an aqueous solution of 2% concentration (w / v) potassium penicillin G (Squibb) (potassic penicillin G) are then circulated through the column. The pH is kept at a value of 8.0, 0.5N NaOH being added continuously using a pH controller. The column is held constant at 37 ⁰ C. After 5 hours, when the rate of soda consumption or the consumption of NaOH is reduced to 1/20 of the original value, the reaction mixture is removed and ^{cooled to 3 °} C., acidified with 2N HCl, up to a pH value of 3, 0 (which requires 33.5 ml of 2N HCl). The reaction mixture is then extracted twice with 200 ml of butyl acetate. In the two organic extracts, the penicillin was determined with hydroxylamine, which required 298 mg in the first extraction and 2 mg in the second.

309846/1 175

Since the total amount of penicillin was 12 g, this corresponds to a yield based on the conversion of 97%. The chromatographic examination showed no decomposition products.

The aqueous phase (800 ml), which did not contain any residual penicillin and which did not contain phenylacetic acid, was adjusted to a pH of 7.0 by adding 33 ml of 2N NaOH and in vacuo at 37 ° C. to a volume concentrated by about 110 ml.

The concentrated 6-APA solution is ^{cooled to 0} ° C. and adjusted to a pH of 4.2 with 3N HCl. 6-APA precipitates and is separated off by filtration and dried in vacuo at 45 ° C. to constant weight. 6.6 g are obtained.

The 6-APA content in the crystallization mother liquors (130 ml) is 0.4% w / v. Under the use of Hydroxylamine produces a crystalline 6-APA product with a yield of 97.5%.

As by IR spectrum, chromatographic investigation, optical rotation has been detected, the product is almost pure. Within six months, they made one hundred 6-APA preparations, working in the same way as described above and always using the same enzymatic Fibers used. No noticeable loss in productivity was observed.

Example 2

It was worked in the same way as described in Example 1, where you:? ch spun filaments that enveloped an enzymatic preparation of E. coli cells, which had been cleaned 15 times as described in Example 1.

309846/1175

An equivalent amount of the enzymatic filament thus obtained showed an activity which was 10 times stronger than that of the filament of the previous example.

In the same column of Example 1 (volume 480 ml) 37 g of fibers are placed. The fibers are mixed with water and Glycerin washed until the wash water was free of protein.

First 3 liters of aqueous solution with a concentration of 2% (w / v) potassium penicillin G (Squibb) are placed in a 5 liter container. The solution is continuously fed into the column with the fibers by a peristaltic pump and passed through a feed container or alimentation container. In order to severely limit penicillin hydrolysis, it is necessary to ensure that the reaction mixture is completely homogenized. Therefore, the feeding vessel is vigorously stirred and the recycled amount is adjusted to 500 ml / 1 '. The pH is kept constant at a value of 8 by adding a 0.5N aqueous NaOH solution via a pH regulator. The temperature of the reaction medium is automatically maintained at 37 ° C via the thermostatic device of the column. The consumption of NaOH solution, which is applied to paper, enables the course of the hydrolysis kinetics to be followed.

After 2 hours and 10 minutes, the rate at which the sodium hydroxide or soda is consumed is reduced to less than 5% of the initial rate. At this point the reaction is terminated and the reaction medium is removed from the circuit. The consumption of 0.5N NaOH solution is approximately 310 ml.

About 3300 ml of aqueous solution, the 6-APA, phenylacetic acid, obtained by penicillin hydrolysis are obtained from the circuit and contains residual penicillin. the

309846/1175

Phenylacetic acid and the penicillin are removed from the reaction medium by extraction with butyl acetate. It is extracted twice with 1100 ml of fresh solvent each time. The reaction medium is placed in a 6 1 container, which is provided with a stirrer, and cooled to 5 ⁰ C and adjusted with a 1N aqueous HCl solution to a pH-value of the third 1100 ml of butyl acetate are then added to the medium and the mixture is stirred in order to obtain good dispersion between the phases (aqueous and organic).

During the stirring, which lasts 15 minutes, 1N HCl is added continuously in order to keep the pH constant. The solution is allowed to ^{settle at 5 °} C. for about 20 minutes. This gives an aqueous phase in the bottom of the reaction vessel which is somewhat cloudy in the form of small drops due to traces of solvent, and a clear organic phase in the upper part. The three phases are separated with a separating funnel and the aqueous phase present in the emulsion of butyl acetate and water is separated off by centrifugation.

The aqueous phases are then combined and again with 1100 ml of fresh solvent is treated in a similar manner to the first extraction and the aqueous one is analogous Phase regained. 180 ml aqueous solution of 1N HCl was used during the two extractions. In the In both butyl acetate fractions, the presence of penicillin was determined with hydroxylamine. In the group obtained in the first extraction, a concentration of 3n / ml was found. In the second faction no penicillin was detected.

The aqueous phase obtained during the extraction is adjusted to a pH of 6.9 with 165 ml of an aqueous 1N NaOH solution and then evaporated in vacuo in a rotary evaporator. The bath of the rotary evaporator is maintained at 45 ⁰ C. The distilling off

309846/1175

Liquid is cooled to -5 ⁰ C. The pressure in the system is 1 mm Hg. Within 5 hours the volume of the aqueous phase is reduced to approximately 1/8 of the original volume.

The residue is placed in a 1 l reaction vessel, ^{cooled to 2 °} C. and adjusted to a pH of 4.2 by adding 6N HCl. During the adjustment of the pH, the 6-APA precipitates in crystalline form. The precipitate is dried off by filtration in vacuo and dried in vacuo (0.5 mm Hg and 45 ° C.) to constant weight. 32.4 g of product are obtained. The mother liquor (450 ml) contains, determined according to the hydroxylamine method, 180 mmol / 16-APA, which corresponds to 0.39% by weight.

The crystalline 6-APA obtained is redissolved in water and the concentration is determined by the hydroxylamine method. The comparison with a standard solution of very pure 6-APA (obtained by repeated crystallization and solutions) showed a titer of 98.5%. From the original 161 mmol penicillin one obtained _{= 147} ^ _{01 6} _ _APA .

Assuming that the starting material was pure, this corresponds to an overall yield of 6-APA of 91.4% of theory.

When working continuously, some of the mother liquor from the crystallization can be recycled and evaporated again in vacuo. In this way, the overall yield of product can be increased to 95% of theory.

Example 3

In a manner similar to that described in Example 1, an enzynifilament is prepared, the crude extract of approximately 100 g contains moist mycelium from a Penicillium chrysogenum family.

309846/1175

30 g of the obtained enzymatic fiber are in the Given column of Example 1 and kept at 37 ° C at constant temperature. 600 ml of an aqueous one is circulated Solution of the potassium salt of penicillin V and maintains the pH value with a device for constant adjustment of the pH at 8.0. Approximately 90% hydrolysis of penicillin V is achieved within 5 to 7 hours was used as the starting material. Numerous attempts have been made over and over again, one being the same Used fiber and did not observe any noticeable loss of activity.

Example 4

The column containing enzymatic fibers described in Example 1 was used and it became ampicillin [6- (D (-) - α-aminophenylacetamido) penicillin].

An aqueous solution obtained in the hydrolysis process described in Example 1 was Penicillin-6 and freed from phenylacetic acid. The solution contained approximately 8.5 mg / ml 6-APA. She gets to a pH adjusted to 6.0 and then added to D-α-Amino- 'phenylacetamide bromohydrate (final concentration 18 mg / ml).

The aqueous solution is circulated through the column, which is kept at a constant temperature of 37 ⁰ C. The pH is maintained around 6.0. After about 6 to 7 hours, ampicillin was obtained in about 90% yield.

Example 5

The procedure was as described in Example 4, but instead of D-ct-aminophenylacetamide bromohydrate Used DL-mandelamide at concentrations of 12 mg / ml and kept the pH around 5.5. After 6 hours one obtained α-Hydroxybenzylpenicillin in a yield of 9O? 6.

309846/1175

Example 6

With stirring, 16 g of ethyl cellulose (Hercules type N-200) were dissolved in 184 g of toluene in a reactor. Was separated an enzyme solution prepared: 60 g of moist E. coli cells were suspended under ultrasonic vibration, centrifuged and the solution was treated with ammonium sulfate. A precipitate was formed, which was dissolved in 30 ml of buffer, containing glycerin was dissolved.

The enzymatic solution thus obtained is added to the polymer solution. The emulsion of the two phases is achieved by vigorous stirring at ⁰ ° C. for 30 minutes. The emulsion is placed in a small spinning vessel which is kept at -6 ° C., and then it is spun under Np pressure. The filaments are coagulated in petroleum ether at 20 ° C.

30 g of enzymatic fibers are used and the procedure described in Example 1 is used. You get in every 5 hours almost constant yield 5115 g of 6-aminopenicillanic acid.

Example 7

In a manner similar to that described in Example 6, an analogous enzymatic preparation is made in poly-γ-methylglutamate (PLF-30 Kjowa Hakko Kogyo Co., Ltd.). The coagulation takes place in toluene at room temperature. 30 g of this enzymatic fiber are produced in the same manner as in Example 1 used to obtain approximately 6 g of 6-aminopenicillanic acid every 5 hours.

Example 8

The reactor described in Example 1, which contained 27 g of enzymatic fibers, was used. To this you gave 600 ml of one 2% aqueous solution (w / v) of the potassium salt of 7- (2-phenylacetamido) cephalosporanic acid. The pH was

309846/1175

held at 8.0 and the temperature was 37 ° C after 5 hours 98% hydrolysis was obtained and 7-aminocephalosporanic acid was isolated from the reaction medium.

Example 9

Using the enzymatic fibers obtained in Example 3, a column was filled with 30 g of the fibers. 600 ml of an aqueous solution and a 2% concentration of the potassium salt of was passed through this column 7- (2-phenoxyacetamido) cephalosporanic acid. After 6 hours, an 85% hydrolysis was obtained and isolated from the 7-aminocephalosporanic acid reaction mixture.

Example 10

The reactor described in Example 1, which contained 37 g of enzymatic fibers, was used. That is how one guided 600 ml of a 2j6igen aqueous solution of the potassium salt of 7- (2-Phenylacetamido) deacetylcephalosporanic acid. The pH was maintained at 8.0 and the temperature at 37 ° C. After 5 hours, the hydrolysis of the substrate was complete and the yield of 7-aminodeacetylcephalosporanic acid was 85%.

Example 11

The reactor described in Example 1, which contained 37 g of enzymatic fibers, was used. 500 ml of an aqueous solution was passed through which contained 5 g of the potassium salt of 7-aminocephalosporanic acid and 13.1 g of D-oc-phenylglycine methyl ester chlorohydrate. The pH was adjusted to 6.5 and kept at this level by a device for keeping the pH constant. The temperature was kept at 37 ° C. After 1.5 hours, HO% of the 7-aminocephalosporanic acid had been converted into 7- (2-D-cc-aminophenylacetamido) -cephalosporanic acid. The term "acilase" means a compound capable of hydrolyzing acyl groups.

309846/1175

Claims (1)

Claims 1. Process for the enzymatic treatment of Antibiotics, characterized in that a mixture which contains an antibiotic such as one from the group natural penicillins, directed into a reaction zone, where they are subject to the action of an enzymatic preparation, embedded in fibers, is subjected, and then the products thus obtained from the mixture, which is the Leaves reaction zone, separates. 2. The method according to claim 1, characterized in that the mixture containing the antibiotic in the Reaction zone is initiated where it is caused by the action of the enzymatic preparation embedded in the fiber is hydrolytically cleaved. 3. The method according to claim 1, characterized in that the mixture containing a product by Hydrolysis of one antibiotic produced is passed into a reaction zone, where it interacts with another Product located in this zone in the presence of an enzymatic preparation embedded in fibers, a Synthesis reaction is subjected. 4. The method according to claim 1, characterized in that the mixture containing an antibiotic, in any Sequence is passed in more than one reaction zone and a hydrolytic cleavage and enzymatic Synthesis by means of an enzymatic preparation, which is embedded in a fiber and at least partially therein is insoluble, is subjected. 5. The method according to any one of the preceding claims, characterized ^ indicates that the feed mixture is a Formula antibiotic 309846/1175 22210A6 R-C-NH-CH- / V / ^CH 3 CH ₃ CO-N CH - COOH where R is an alkyl group having 1 to 10 carbon atoms or an alkenyl group. with 3 to 10 carbon atoms or an aralkyl group or the groups R · -OCH ₂ - or R'-SCH ₂ -, in which R ^{1 is} an alkyl, alkenyl, phenyl or halogen, NO ₂ , alkyl, alkenyl, alkoxy means monosubstituted phenyl group. 6 «The method according to claim 5, characterized in that that the feed mixture containing the antibiotic is passed into a hydrolysis zone, for example as aqueous solution, preferably at concentrations greater than 1%, expressed as the weight of the antibiotic per volume Solvent. 7. The method according to claim 5, characterized in that the concentration is preferably not higher than 6% , expressed as the weight of the antibiotic per volume of solvent. 8. The method according to claim 5, characterized in that the concentration is preferably maintained between 2 and 3% _{t in} terms of weight per volume. 9. The method according to claim 6, characterized in that the solution of the antibiotic in the hydrolysis zone a pH value in the range of 8, i.e. close to 8, is maintained, 10. The method according to claim 6, · characterized in that the solution of the antibiotic in the hydrolysis zone as buffered solution is passed. 309 8 46/1175 11. The method according to any one of the preceding claims, characterized in that the enzymatic preparation which is encased by fibers and used in the reaction zone contains enzymes that are present in raw extraction, which are obtained from molds and molds Actinomycete cells had received or that this contains enzymes that are present in extracts made from Bacterial cells originate or that the enzymes used by purification from the above-mentioned compositions were obtained, and that fibers are used which are made from esterified cellulose polymers, nitrates, polyolefins, Methacrylates, vinylic esters, vinyl chloride, vinylidene chloride, Styrene, polyamides and butyral polyvinyl were produced and the embedding was carried out by a viscous phase consisting of enzyme and the easy-to-spin polymeric material is spun. Process for the preparation of 6-aminopenicillanic acid, characterized in that a natural Penicillin formula R-C-NH-CH-CH C CH ₃ CO-N CH - COOH wherein R has the meanings given above, passes into a reaction zone in which an enzymatic Preparation which is enveloped by fibers, is, and this has the above-mentioned composition, and one then the 6-aminopenicillanic acid of the formula obtained from the hydrolysis products 309846/1 175 CH, NH ₂ -CH-CH C CO-N CH - COOH isolated. 13. The method according to any one of the preceding ^ ". Claims, characterized in that a solution of a penicillin compound or penicillin compound or a solution of a penicillin hydrolysis product is passed into a reaction zone where it is in the presence of another product is subjected to synthesis under the action of an enzymatic preparation embedded in fibers. 14. The method according to claim 13, characterized in, that 6-aminopenicillanic acid is used as the penicillin hydrolysis product, which is passed into a reaction zone, where they undergo a synthesis reaction with the desired carboxylic acid or its amide under the action of an enzymatic Preparation embedded in fibers is subjected, the enzyme and the fibers being among those indicated above to be selected. 15. The method according to claim 14, characterized in that that the feed solution of the penicillin compound or the penicillin hydrolysis product into a reaction zone and has a concentration, expressed as compound / solvent, which is preferably higher is than 1%, expressed as compound weight per Volume of solvent. 16. The method according to claim 15 ₉ characterized in that the concentration of the feed solution that is used, is preferably between 1 and 3%, expressed as weight of compound per volume of solvent. 309846/1175 17. Process according to claim 13, characterized in that the pH value in the synthesis zone is regulated or controlled will. 18. The method according to claim 14, characterized in that that the pH in the synthesis zone is kept at a value close to 6. 19. The method according to claim 14, characterized in, that the feed product 6-APA, the product with which the synthesis is carried out, oc-hydroxybenzylpenicillanic acid used, and that the enzymatic preparation used is derived from E. coli cells and the fibers from cellulose triacetate are made. 20. The method according to claim 14, characterized in that there is used as the feed product 6-APA that the The product with which the synthesis is carried out is ampicillin and that the enzymatic preparation from E. coli cells and the fibers are made from cellulose triacetate. 21. The method according to any one of the preceding claims, characterized in that natural penicillin in at least one first reaction zone is passed, where it is under the action of at least one enzymatic Preparation is cleaved and where the cleavage products are separated and the product that forms the penicillin skeleton contains or is penicillinic type, is passed into at least a second reaction zone, where it is with at least another compound is reacted, in which case the products of this second reaction zone are subjected to the separation process are subjected and the synthesized penicillin is isolated. 309846/1175 - ²¹ - 222Ί 22. The method according to any one of the preceding claims, characterized in that the hydrolysis and synthesis zone are preferably operated at temperatures which are not higher than 60 ^° C. and preferably at temperatures in the range between 37 and 40 ^° C. 23. Compounds, either fully or partially prepared according to one or more of the preceding Expectations. 24. Process for the enzymatic treatment of antibiotics, characterized in that a mixture containing an antibiotic from the group of cephalosporins contains, passes into a reaction zone where it is exposed to an enzymatic compound present in fibers is embedded, is subjected, and that then from the mixture which leaves the above-mentioned reaction zone, the product obtained is separated off. 25. The method according to claim 24, characterized in that that the potassium salt of 7- (2-phenylacetamido) -cephalosporanic acid is used as the feed product and that the product obtained is 7-aminocephalosporanic acid. 26. The method according to claim 24, characterized in that that the potassium salt of 7- (2-phenoxyacetamido) -cephalosporanic acid is used as the feed material and that 7-aminocephalosporanic acid is obtained as the product. 27. The method according to claim 24, characterized in that the potassium salt of 7- (2-Phenylacetamido) -deacetylcephalosporanic acid is used and that the product 7-aminodeacetylcephalosporanic acid receives. 309846/1175 28. The method according to claim 24, characterized in that that a mixture of the potassium salt of 7-aminocephalosporanic acid and D-α-phenylglycine methyl ester chlorohydrate is used as the feed material used and that the product obtained is 7- (2-D-α-aminophenyla c etamido) -cephalosporanic acid. 309846/1175