DE1077657B - Process for the production of tetracyclines - Google Patents

Description

Process for the preparation of tetracyclines The invention relates to a new process for the preparation of the antibiotics, tetracycline, chlortetracycline and bromotetracycline. These tetracyclines have the formula wherein Z is hydrogen, chlorine or bromine. So far, they have been produced by aerobic fermentation of an aqueous nutrient medium, which has a certain content of chlorine and / or bromine ions, with a microorganism of the species Streptomyces aureofaciens.

It has now been found that the Tetracyclin.e of the formula I can be prepared if an aqueous nutrient medium with a microorganism of the species Streptomyces aureo.faciens in the presence of the corresponding S a (11 a) -D @ ehydrotetracycline of the general formula wherein Z has the meaning given above, aerobically fermented.

The 5 a (11 a) -Dehydrotetracycline of the general formula II are new Antibiotics. They are made in the presence of certain fermentation conditions under suitable fermentation conditions mutant strains of Streptomcyes aureofaciens.

The biological activity of the 5a (11 a) -dehydrotetracyclines is right low: However, since the new mutated strains of Streptomy ces aureofaciens are good Provide yields of the desired 5a (11 a) -dehydrotetracyclines, z. B. mostly generate more than 9,000 to 10,000 y / ml of 7-chlorine, -5 a (11 a) -dehydrotetracycline, Attempts have been made to convert these antibiotics into those already known. , therapeutic convert valuable tetracyclines. ' The invention solves this problem through biological Reduction of the new 5 a (11 a) -dehydrotetracyclines. As described in detail below becomes, 7-chloro-S a (11 a) -dehydrotetracycline in 7-chlortetracy clin, 5 a (11 a) -dehydrotetracycline converted into tetracycline and 7-bromo-5 a (11 a) -dehydrotetracycline into 7-bromo tetracycline.

The process according to the invention can be carried out by simply adding the dehydrotetracyclines to a fermentation solution in which common strains of Streptomyces aureofaciens can be used. So 7-chloro-5 a (11 a) -dehydrotetracycline by Addition to a common fermentation solution, the common chlortetracycline producing strains Contained by Streptomyces aureofaciens, converted to chlortetracycline. The transformation is not yet complete, but 18 to 48% conversions have been made into scored in most cases. - Similarly, 7-bromo-5 a (11 a) becomes -dehydrotetracycline when added to a fermentation solution, the usual strains of Streptomyces aureofaciens- contains, converted to bromotetracycline and 5a (11a) -dehydrotetracycline to tetracycline.

The fermentation conditions are generally the same as one in known processes for the production of chlortetracycline .. and tetracycline fermentative route used: The 5 a (11 a) -De = hydrotetracyclines are preferred added at the beginning of the fermentation process. The fermentation medium contains the usual nutrients and mineral substances. Suitable nutrient substances are, for example Strength, Dextrose, cane sugar, glucose, molasses, soybean flour, peanut flour, yeast, meat extracts, Peptone, ammonium sulfate, urea, corn steep liquor, liquid - residues from the Brandy distillation, fish meal and other common - substances. To the used inorganic salts include, for example, calcium carbonate, ammonium sulfate, ammonium chloride, Sodium dihydrogen phosphate and the various trace elements such as manganese, cobalt, Zinc, copper or iron.

The other fermentation conditions, such as hydrogen ion concentration, temperature, "time, rate of aeration, preparation of the vaccine, sterilization, inoculation and the like. Are of the usual type. They are similar to those described in U.S. Pat in U.S. Patent 2,734,018 for the manufacture of tetracycline.

The production of chlortetracycline and tetracycline works in the same way from the fermentation medium in the usual way and does not need to be described here to become. The methods for obtaining these antibiotics from fermentation fluids are numerous has been described. Bromtetracycline can be obtained in a similar manner.

It should be noted that some, described in the examples Fermentation attempts were made in the presence of certain inhibitors, for example in the presence of 2,5-dimercapto-1,3,4-thiadiazole or 2- (2-furyl) -5-mercapto-1,3,4-oxadiazole. These inhibitors cause a change in the ratio of. Chlortetracycline to tetracycline in the normal fermentative production of chlorotetracycline, which is used for same time is going on, so that a high percentage of tetracycline by the normal fermentation is obtained. One can. so the formation of chlortetracycline Monitor 7-chloro-5a (11 a) -dehydrotetracycline more easily. In the absence of such Inhibitors could be the formation of chlortetracycline from 7-chloro-5 a (11 a) -dehydrotetracycline go on unobserved.

The following examples illustrate the invention. Example 1 A fermentation medium of the following composition is prepared: Starch ................... 55 g / 1 corn steep liquor .......... 25 g / 1 approx C 03 ................... 9 g / 1 (NH4) 2S04 .............. 5.6 g / 1 Mn S 04 (709o) ........... 80 mg / 1 Co 02-6 H2 O ............ 5 mg / 1 N H4 Cl ..... .............. 1.7 g / 1 lard ......... 3.2 percent by volume After sterilization of the medium, 25 ml of it are poured into a 250 ml Erlenmayer Flask inoculated with a vegetative vaccine of Streptomyces aureofaciens (strain S 77). 100 parts of 2,5-dimercaptor 1,3,4-thiadiazole per million parts and 500 y of 7-chloro-5a (11a) -dehydrotetracycline per ml are added and the fermentation is carried out for 120 hours at 25 ° C. on a rotating shaker. The mash is fluorometrically analyzed for its chlorotetracycline content. In the fluorometric analysis, one finds a dehydrotetracycline due to the addition of 7-chloro-5 a. (11 a) -, dehydrotetracycline. Increase of 248 7 / ml, which is 48% of the theoretical conversion of 7-chloro-5 a (11 a) -dehydrotetracycline to chlorotetracycline.

Example 2 The procedure of Example 1 is repeated with the sole exception that 10 parts per million of 2- (2-furyl) -5-mercapto-1,3,4-oxadiazole are added to the medium as an inhibitor. The fluorometric analysis for chlorotetracycline shows an increase of 170 μg / ml due to the addition of 7-chloro-5 a (11 a) -dehydrotetracycline. This means 34% of the theoretical conversion of the added 7-chloro-5 a (11 a) -dehydrotetracycline into chlortetracycline. Example 3 The procedure of Example 1 is repeated with the exception that 5a (11a) -dehydrotetracycline is added to the fermentation system and no inhibitor is used. The medium is inoculated with a vegetative vaccine from Streptomyces aureofaciens (strain S77). The conversion of the 5 a (11 a) -dehydrotetracycline added to the tetracycline is approximately 35%. Example 4 The procedure of Example 1 is repeated with the exception that 7-bromo-5a (11a) -dehydrotetracycline is added to the fermentation system; the medium is inoculated with a vegetative strain of Streptomyces aureofaciens (strain S 77). The conversion of the added 7-bromo-5a (11a) -dehydrotetracycline to bromotetracycline is approximately 30%.

Claims (1)

PATENT CLAIM: Process for the production of tetracyclines of the general formula wherein Z is hydrogen, chlorine or bromine, characterized in that an aqueous nutrient medium with a microorganism of Streptomy ces aureofaciens in the presence of a corresponding 5 a (11 a) -dehydrotetracycline of the general formula where Z has the meaning given above, aerobically fermented.