SE188594C1 - - Google Patents

Description

Inventors: J R D McCormick and E R Jensen Priority requested from November 5, 1957 and July 28, 1958 (USA) The present invention relates to an improved process for hydrogenolysis. of 6-hydroxyhydronaphthacenes. In particular, the invention relates to the hydrogenolysis of compounds having a tetracycline nucleus.

In particular, the invention relates to a process for the catalytic reduction of a 6-hydroxyhydronaphthacene to the corresponding 6-deoxy derivative, which is characterized by bringing a solution of a 6-hydroxyhydronaphthacene in a polar solvent into contact with hydrogen gas in the presence of a finely divided rhodium catalyst, until the 6-hydroxy group is reduced, and then the 6-deoxy derivative formed is isolated.

According to a particularly suitable embodiment of the invention, 6-hydroxyhydronaphthacene, which contains acid-containing groups in the 11- and 12-position in the hydronaphthacene array, is prepared. 6-deoxytetracyclines. These new compounds have the structural formula H RI R2 41 R3 R4 N / N / \ „/ / \ H / \ \; vale or hydroxy and R 3 and R 4 denote vate or dimethylamino with the proviso that having at the same time does not denote Nate or dimethylamino and 112 denotes hydroxy only when R 1 is a methyl group.

As compounds corresponding to the above general formula, there may be mentioned 6-deoxytetracycline, 6-deoxy-4-epi-tetracycline, 6-deoxyoxytetracycline, 6-deoxy-4-epi-oxytetracycline, 6-demethyl-6- deoxytetracycline and 6-demethyl-6-deoxy-4-epi-tetracycline. The new deoxytetracyclines 5.ro biologically active and have a remarkable activity against a number of gram-positive and gram-negative microorganisms. The above compounds have the same typically broad antibacterial spectrum as tetracycline, which is very surprising in view of the fact that the new compounds do not contain a hydroxyl group in the 6-position in the tetracycline nucleus and that some of them also contain a methyl group less.

As described in the above-mentioned patent, the new compounds are prepared by hydrogenolysis of the corresponding tetracycline with hydrogen gas in the presence of metallic palladium or any other platinum group metal. An essential feature of the process according to the above patents is that the hydrogenolysis reaction must be carried out in the presence of a complexing agent, such as boric acid or boron trifluoride, which serves to prevent hydrogenation of the oxygen functions in the 11-position and 12-position in the tetracycline ring system. If the 11- or 12-positions in the tetracycline nucleus are hydrated four times before the 6-position, which always occurs in a normal hydrogenation reality, the resulting compound may be complete without biological activity. The use of chelating agents, however, has the consequence that these two. Oxygen functions are bound to prevent their hydrogenation, so that the desired antibacterial activity of the resulting compound is maintained.

According to another particularly suitable embodiment of the invention, starting from a 6-hydroxy-hydronaphthacene belonging to the tetracycline series and bearing the structural formula RHO R1 R2 H R3 Rd "OH / II \ / \ 11OH OH 0 OH 0 or frail an acid addition salt thereof this starting compound to a 6-deoxy derivative of the tetranycline series of the formula RHR1RZHR3R2 \, - / H \ IHV / \ /, OH / CI— ONH2 N denotes vale or hydroxy, R2 and Rd denote vale or dimethylamino with the proviso that both may not be vale or dimethylamino, and van R denotes vate or chlorine or bromine, wherein R2 denotes only a hydroxy group, where R is vate and R1 is methyl.

For the preparation of the new halogenoxytetracyclines according to the invention, i.e. 7-chloro-6-deoxy-tetracycline, 7-bromo-6-deoxytetracycline, 7-chloro-6-demethyl-6-deoxytetracycline and 7-bromo-6-demethyl-6-deoxytetracycline or their excipients of the corresponding 7-bromo- or 7-chlorotetracycline, it is necessary to stop the hydrogenolysis reaction, but about 1 mole of hydrogen is absorbed, otherwise the 7-chloro or 7-bromine atoms are removed at the same time as the 6-hydroxy group, which results in the formation of a 6-deoxytetracycline. By carefully regulating the hydrogenation conditions, however, it is possible to maintain the 7-chloro or 7-bromine atoms unchanged, so that the new halogenated deoxytetracyclines are formed.

If about 2 moles of hydrogen are absorbed per mole of tetracycline derivative, the 7-chloro or 7-bromine atom is substantially completely removed.

It is extremely surprising that the 6-deoxytetracyclines still exhibit gamma typical broad antibacterial spectra as tetracycline, especially considering that anhydrotetracycline, which also has a smaller hydroxy group in the 6-position in the tetracycline nucleus, has a significantly lower antibacterial activity. tetracycline, namely only 1 / 10-1 / 4 as much activity as 6-deoxytetracycline (turbidimetric test against S. aureus). In addition, it is completely unexpected that a compound which does not contain the methyl and hydroxy groups of tetracycline would be a more active antibacterial agent than the tetracycline itself. It is thus now clear that the antibacterial activity of tetracycline (turbidimeric test against S. aureus) remains essentially unchanged by replacing the 5-hydrogen atom with the OH, 6-hydroxy group with the H, 6-methyl group with the H or the 7-hydrogen atom with the Cl or Br.

Replacement of the 6-hydroxyl group in tetracycline, 5-hydroxytetracycline and 6-demethyltetracycline has now been extended to the remaining members of this group of tetracycline antibiotics, namely 7-chlorotetracycline, 7-bromotetracycline, 7-chloro-bromo-6-demethyl-demethyl -demethyltetracycline. The present invention thus encompasses the preparation of the novel compounds 7-chloro-6-deoxytetracycline, 7-chloro-6-deoxy-4-epi-tetracycline, 7-bromo-6-deoxytetracycline, 7-bromo-6-deoxy-4-epi -tetracycline, 7-chloro-6-demethyl-6-de-oxytetracycline, 7-chloro-6-demethyl-6-deoxy-4-epi-tetracycline, 7-bromo-6-demethyl-6-deoxytetracycline and 7-bromo -6-demethyl-6-deoxy-4-epitetracycline.

The neutral products according to the invention can be transferred to a mineral acid salt, I. e.g. to the hydrochloride, by treatment with acids, e.g. hydrochloric acid, at a pH below about 4. Other acid salts, such as the sulfate, phosphate, trichloroacetate, oxalate, citrate, glyconate, etc., can be prepared in a similar manner. The 6-deoxytetracycline is conveniently suspended in a suitable solvent during the acidification.

The alkali metal and alkaline earth metal salts can be readily prepared by treating the amphoteric compound with about 1 equivalent of the selected base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide and the like. The metal salts can be produced in aqueous solution or in another suitable solvent. The basic salts are suitably prepared at a pH of 6 or higher. The free base can be obtained at a pH value between about 4 and 6.

Complexes, such as 6-deoxytetracycline-aluminum glyconate complex, can be prepared by simply mixing the hydrochloride salt of a 6-deoxytetracycline with aluminum glyconate in an aqueous solution. The formation of the new complexes can thus easily be achieved in essentially the same way as the previous edge for the removal of similar complexes with other tetracycline antibiotics, / - —3 e.g. those described in U.S. Patent No. 2,736,725.

The novel antibiotics of the invention also have an epimeric form at the 4-carbon atom of the tetracycline nucleus, namely the same form as described in connection with other tetracycline compounds. These new isomers can be easily prepared by installing the water ion concentration in a concentrated solution of the normal compound to between pH 3.0 and 5.0 after which the solution is allowed to stand until the isomerization has taken place to an equilibrium state. This process for the preparation of the new isomers is analogous to the process used in the conversion of the previously known tetracyclines to their epimers [J. A. C. S. 79, pp. 2849 (1957)]. - The isomerization is suitably carried out at runic temperature, but a higher conversion rate can be achieved at higher temperatures. The pH value Mir should be between about 3.0 and 5.0 and preferably between 3.5 and 4.5. Some epimerization occurs at a water ion concentration outside these limits and also in distilled water, but the velocity is very slow. The concentration of antibiotics in the aqueous solution should be as high as possible in order to increase the rate of epimerization. Full tooth equilibration may require about 24 hours at 25 ° C, but a complete equilibrium may require a considerably shorter time under special conditions. However, the basin results are usually obtained by allowing the solutions to stand for about a week or longer. An iron weight state seems in most cases to be reached at about 50 go, ie. when about half of the amount of antibiotic is converted to the epimer at equilibrium.

Because concentration is an important factor, if high yields are to be obtained in a short time, we must choose a solvent system which gives the highest possible concentration of the antibiotic. These solvent systems should be buffered to a pH value within the appropriate range. Examples of suitable solvents are methanol, ethanol, butanol, acetone, 2-ethethanol, 2-methoxypropanol, glacial acetic acid, tetrahydrofuran, dimethylformamide and mixtures of these solvents. Other solvents can also be used. A particularly suitable buffer agent is sodium divate phosphate, but other buffering agents and buffer pairs are also used, which maintain the water ion concentration within the desired range.

It is also possible to prepare the novel 6-deoxy-4-epi-tetracyclines according to the invention by catalytic reduction of the corresponding 4-epi-tetracycline. The 4-epi-tetracyclines are described in J. A. C. S. 79, p. 2849 (1957). According to this embodiment of the invention, the hydrogenolysis reaction is carried out using a 4-epi-tetracyldine on exactly the same salt as described above before the hydrogenolysis of tetracycline. After complete hydrogenation, the corresponding 6-deoxy-4-epi-tetracycline is formed.

According to the present invention, it has been found that when using rhodium as a catalyst, either finely divided metallic rhodium or rhodium in the form of a suspension on a suitable carrier, such as activated trachol, alumina and the like, quite surprisingly need not use any complexing agent. agent or some chelating agent feu- to bind the oxygen functions in the 11- and 12-position, and that the desired hydrogenolysis. of the 6-hydroxy group takes place uniformly with a good yield of the corresponding 6-deoxytetracycline. a responsible purification step and can obtain pure products in good yield. In the processes described in the above-mentioned patents, it has been found that it is very difficult to remove residual amounts of these complexing medals by ordinary extraction and purification. As stated, extraclion and purification problems are eliminated by using the new catalyst according to the invention. However, the use of rhodium provides an additional advantage over the use of metallic palladium, which consists in the fact that with the new catalyst a wider pH range can be used in the hydrogenolysis reaction described.

The invention is described in more detail in the following, in which mainly the talk is about hydrogenolysis of compounds with the tetracycline tanks. It should be noted, however, that this only occurs for ash-damaging andamal, since the described hydrogenolysis reaction can be applied with the same result using other 6-hydroxyhydronaphthacenes or starting materials.

The novel hydrogenolysis reaction of the invention can be carried out by contacting the selected tetracycline compound, which is in solution in a polar solvent, with vale in the presence of finely divided rhodium as catalyst. As stated above, the pure rhodium metal can be used, but it is also possible and in all-manila more convenient to suspend the catalyst on any ordinary bar, such as finely divided alumina oxide, activated carbon, diatomaceous earth, etc. The hydrogenolysis can be carried out at a temperature between about 100 ° C and is carried out preferably from about room temperature, about 25 ° C, to about 35 ° C and at a water gas pressure of from 1 to 140 atm.

As examples of suitable inert solvents, there are various polar solvents, such as water, dioxane, glacial acetic acid, 2-methoxyethanol, 2-ethoxyethanol, ethyl acetate, etc. A mixture of water and dimethylformamide in the ratio 1: 1 has shown be a particularly suitable solvent mixture for this reaction. A catalyst concentration of at least 5% by weight, calculated on the tetracycline, is undesirable and up to about 400% by weight can be used. The hydrogenolysis is usually carried out until 1 mole of vale is absorbed when tetracycline is the starting material; after uptake of this amount of cotton, the rate of absorption has a tendency to decrease. If starting from chlorotetracycline and the chlorine atom is to be removed, it is of course necessary to take up 2 moles of cotton. A certain amount of care must be taken not to continue the hydrogenolysis for an illegally long time, as continued and unintended reduction can lead to ruin in sa. cases of formation of less harmful products.

After completion of hydrogenolysis, the formed 6-deoxytetracycline compound is isolated in a suitable manner, e.g. by separating the catalyst and concentrating the solution. The product can be evaporated to dryness, purified by fractional precipitation in methanol and can be further purified by recrystallization from alcohol on its own edge.

The invention is further illustrated by the following examples.

Example 1. 0.5 g of tetracycline hydrochloride is dissolved in 10 ml of attic acid. This solution was continued with 2.0 g of 5% rhodium alumina, after which the resulting mixture was contacted with an excess of hydrogen gas at a pressure of 2.1 kp / cm 2 for 3 hours and then filtered. Spectrophotometric and paper chromatographic analyzes show the presence of 6-deoxytetracycline in the filtrate. Yield 10%.

Example 2. 0.5 g of neutral chlorotetracycline is dissolved in 12 ml of a mixture of dimethylformamide and water in a ratio of 1: 1, after which the plywood is installed at 9.0-9.5 with triethylamine. The solution was continued with 1.0 g of 5% rhodium alumina. The resulting mixture is contacted with an excess of hydrogen gas at a pressure of 2.1 kp / cm 2 for one hour and filtered, after which the pH of the filtrate is installed at about 3.0 with hydrochloric acid. Spectrophotometric and paper chromatographic analysis show the presence of 6-deoxytetracycline in the filtrate.

Example 3. 0.5 g of tetracycline hydrochloride is dissolved in 12 ml of a mixture of dimethylformamide and water (1: 1). This solution was continued with 2.0 g of 5% rhodium carbon. The resulting mixture is contacted with an excess of hydrogen gas at a pressure of 2.1 kp / cm 2 for 16 hours and filtered. Spectrophotometric () eh paper chromatographic analysis shows the presence of 6-deoxytetracycline in the filtrate.

Example 4. 0.5 g of tetracycline hydrochloride is dissolved in 12 ml of a mixture of dimethylformamide and water (1: 1). The solution was continued with 1.0 g of 5% rhodium carbon. The resulting mixture is contacted with an excess of hydrogen gas at a pressure of 2.1 kp / cm for 16.5 hours and then filtered. Spectrophotometric analysis of this filtrate shows that 6-deoxytetracycline hydrochloride is formed in 35% yield. The filtrate is evaporated to a semi-dry state and then dissolved anyo in 10 ml of distilled water and lyophilized. The product is dissolved in 4 ml of methyl alcohol, after which the solution is concentrated to a volume of 0.5 ml. A few drops of concentrated hydrochloric acid are then added and inoculated to initiate crystal formation. On delta sat extracted. 50 mg of 6-deoxytetracycline hydrochloride crystals, which on spectrophotometric analysis are found to have an activity of 985 micrograms / mg.

Example 5. 5.18 mg of 7-chloro-6-demethyl-tetracycline hydrochloride [J. A.C.S. 79, p. 4561 (1957)] is dissolved in 4 ml of a 1: 1 mixture of dimethylformamide and water, after which the solution is continued with 10.54 mg of 5% rhodium carbon. The resulting mixture is contacted with an excess \ taigas for 5.5 hours and filtered. Spectrophotometric and paper chromatographic analysis show the presence of 6-demethyl-6-deoxytetracycline in the filtrate. Yield 15%.

Example 6. 0.5 g of 4-epi-tetracycline J. A. C. S. 79, p. 2849 (1957)] is dissolved in 10 ml of acetic acid, 2 ml of water and 0.05 ml of perchloric acid. The solution was continued with 2.0 g of 5% rhodium alumina. The resulting mixture is contacted with an excess of gas at a pressure of 2.1 kp / cm 2 for 3 hours and filtered. Spectrophotometric and paper chromatographic analysis show the presence of 6-deoxy-4-epitetracycline in the filtrate. Yield 10%.

Example 7. The experiment of Example 6 is repeated but using 0.5 g of 4-epichlorotetracycline [J. A. C. S. 79, pp. 2849 (1957)]. The compound is contacted with an excess of hydrogen gas. In the presence of rhodium, as described in Example 6. Spectrophotometric and paper chromatographic analysis shows the presence of 6-deoxy-4-epi-tetracycline.

Example 8. The experiment of Example 6 is repeated using 0.5 g of 4-epi-bromotetracycline [J. A. C. S. 79, pp. 2849 (1957)]. This compound is contacted with hydrogen gas as described in Example 6. Spectrophotometric and paper chromatographic analysis show the presence of 6-deoxy-4-epi-tetracycline.

Example 9. The experiment of Example 6 is repeated but using 4-epi-oxytetracycline [J. A. C. S. 79, pp. 2849 (1957)]. The compound is contacted with the hydrogen gas described in Example 6, after which the reaction mixture is filtered. Spectrophotometric and paper chromatographic analysis show the presence of 6-deoxy-4-epi-oxytetracyldine in the filtrate. Yield 15%.

Example 10. The experiment of Example 5 is repeated but using chlorotetracycline hydrochloride as starting material. The hydrogenolysis is carried out in the manner described in Example 5, with 6-deoxytetracycline. formed in a yield of 10%.

Example 11. The experiment of Example 5 is repeated but using bromotetracycline as starting material. The hydrogenolysis is carried out as described in Example 5 to give 6-deoxytetracycline.

Example 12. 5.18 mg of 6-demethyl-4-epi-tetracycline [J. A. C. S. 79, p. 4561 (1957)] is dissolved in 4 ml of a 1: 1 mixture of dimethylformamide and water, after which the solution is continued with 10.54 mg of 5% rhodium carbon. The resulting mixture is contacted with an excess of hydrogen for 5.5 hours and filtered. Spectrophotometric and paper chromatographic analysis show the presence of 6-demethyl-6-deoxy-4-epi-tetracycline in the filtrate. Yield 25%.

Example 13. 5.18 mg of 7-chloro-6-demethyl-4-epi-tetracycline [J. A. C. S. 79, p. 4561 (1957)] is dissolved in 4 ml of a 1: 1 mixture of dimethylformamide and water, after which the solution is fortified with 10.54 mg of 5% rhodium carbon. The resulting mixture is contacted with excess hydrogen gas for 5.5 hours and filtered. Spectrophotometric and paper chromatographic analysis shows the presence of 6-demethyl-6-deoxy-4-epi-tetracycline in the filtrate. Yield 15%.

Example 14. 0.5 g of 5-hydroxytetracycline hydrochloride (Terramycin hydrochloride) is dissolved in 12 ml of a 1: 1 mixture of dimethylformamide and water, after which the solution is continued with 1.0 g of 5% rhodium carbon. The resulting mixture is contacted with excess hydrogen gas at a pressure of 2.1 kp / cm 2 for 16.5 hours and filtered. Spectrophotometric testing of this filtrate shows that 5-hydroxy-6-deoxytetracycline hydrochloride Midas in 32% yield.

Example 15. 0, g neutral 6-demethyltetracycline [J. A. C. S 79, p. 4561 (1957)] is dissolved in 12 ml of a 1: 1 mixture of dimethylformamide and water, after which the pH is adjusted to 2.2 with concentrated hydrochloric acid. The solution was continued with 1.0 g of 5% rhodium carbon. The resulting mixture is contacted with an excess of hydrogen at a pressure of 2.1 k / cm 2 for 16 hours and filtered. Spectrophotometric testing of the filtrate shows that 6-demethyl-6-deoxytetracycline hydrochloride is formed in 26% yield. Pair chromatography shows joke flagon remaining 6-demethyltetracycline hydrochloride.

Example 16. To 240 ml of dimethylformamide, acidified by the addition of 1.0 ml of concentrated hydrochloric acid, are added g 7-chlorotetracycline and 10 g of 30% rhodium chloride-char (activated trachol). The mixture is brought into contact with hydrogen gas at a pressure of 3.36 km2 by about 2 hours of shaking. After filtration, the filtrate is found to contain 7-chloro-6-deoxytetracycline, 6-deoxytetratetracycline and 7-chlorotetracycline. The mixture is separated by preparative paper chromatography to give pure 7-chloro-6-deoxytetracycline in a yield of%. The product shows significant activity against Bacillus cereus ATCC 10702.

Example 17. The experiment In Example 16 is repeated with any addition of 7-bromotetracycline in place of 7-chlorotetracycline, whereby a mixture containing part of the dipped 7-bromo-6-deoxytetracycline is formed. 7-Bromo-6-deoxytetracycline is separated by preparative paper chromatography. Yield 15%.

In Examples 16 and 17 above, it is possible to simultaneously use 1.5 g of boric acid as a chelating agent.

Example 18. Preparation of 7-chloro-6-deoxy-4-epi-tetracycline. 7-Chloro-6-deoxytetracycline, obtained according to Example 16, was added to 1 ml of glacial acetic acid. The mixture is shaken and allowed to stand until equilibrium is reached at room temperature for 18 hours. The epimer is obtained in about 40% yield.

Example 19. Preparation of 7-bromo-6-deoxy-4-epi-tetracycline. 7-Bromo-6-deoxytetracycline according to Example 17 was added to 1 ml of glacial acetic acid, then the mixture. stand and stand in equilibrium at room temperature for 18 hours. The epimer is obtained in a yield of about 40%.

Example 20. To 240 ml of dimethylformamide, acidified by the addition of 1.0 ml of concentrated hydrochloric acid, is added 10 g of 7-chloro-6-demethyl-tetracycline [J. A. C. S. 79, p. 4561 (1957)] and 10 g of 30% rhodium-carbon hydrogenation catalyst. The mixture is contacted with hydrogen gas at a pressure of 3.4 kp / cm 2 for 1 3/4 hours and filtered. The filtrate is developed by paper chromatography with a mixture of chloroform and n-butanol in the ratio 20:80 for 5 hours, whereby 7-chloro-6-demethyl-6-deoxytetracycline is obtained in about 15% yield. The identity of 7-chloro-6-demethyl-6-deoxytetracycline is shown by catalytic hydrogenolysis in alkaline ethylene alkyl carbon monoethyl ether to give 6-demethyl-6-deoxytetracycline and chloride ions. Yield 15%.

Example 21. The experiment of Example 20 is repeated but using 7-bromo-6-demethyltetracycline instead of 7-chloro-6-demethyltetracycline, whereby 7-bromo-6-demethyl-6-deoxytetracycline is formed in a yield of 15%. In the phosocene of Examples 20 and 21, 2.5 g of calcium chloride can be used as the chelating agent.

Example 22. Preparation of 7-chloro-6-demethyl-6-deoxy-4-epi-tetracycline. 6-7-Chloro-6-demethyl-6-deoxytetracycline according to Example 20 was added to 1 ml of glacial acetic acid, after which the mixture was shaken and allowed to equilibrate at room temperature. The epimer is formed in about 35% yield.

Example 23. Preparation of 7-bromo-6-demethyl-6-deoxy-4-epi-tetracycline. 7-Bromo-6-demethyl-6-deoxytetracycline according to Example 21 was added to 1 ml of glacial acetic acid, after which the mixture was shaken and allowed to equilibrate at room temperature. The epimer is obtained in a yield of about 35%.

Claims (15)

Patentanspra.k: A process for the preparation of 6-deoxytetracycline of the general formula Rs H R1R2H Rs 11,, A \ // 6 \ / "7 \ /// 4 \ / OH 3 \ ■ 97 OH OH 0 OH 0 van R 1 represents vac or a methyl group, 112 represents vale or a hydroxy group, R 5 and R 4 represent vate or a dimethylamino group and R represents hydrogen, chlorine or bromine, with the proviso that R 5 and R 2 do not represent vale or dimethylamine groups. and that R 2 is only a hydroxy group when Rdr vale and R 1 is a methyl group, and their salts, may be characterized in that a tetracycline of the structural formula B 3 HO R 1 li 2 H R 3 R 1 z // \ // \\ / \ / OH II IOH ii- OH 0 OH 0 wherein 14, R2, R3, 114 and Rha have the indicated meaning, or an acid salt thereof is reduced in solution in a polar solvent in the presence of a finely divided rhodium catalyst at a temperature between 0 and 100 ° C and at a vatgastryek of 1-140 at. 2. A process according to patent 1, characterized in that R 5 in the formula given in claim 1 is chlorine or bromine in the 6-hydroxy-hydronaphthacene and that the reduction is carried out until about 1 mole of irate is taken up per mole of 6-hydroxy-hydronaphthacene , whereby the R 5 group in the 6-deoxytetracycline after the reduction still consists of chlorine or bromine. 3. A process according to claim 1, characterized in that Rutgor chlorine or bromine in the 6-hydroxyhydronaphthacene and that the reduction is carried out until approximately 2 moles of vale are absorbed per mole of 6-hydroxyhydronaphthacene, whereby the R 5 group in the 6-deoxytetracycline formed consists of irate. A method according to any one of the preceding claims, characterized in that the rhodium is suspended on a carrier. 5. A process according to any one of claims 1-4, characterized in that the solvent for the solution consists of a mixture of equal volumes of water and dimethylformamide. Process according to any one of claims 1, 5, characterized in that the catalyst concentration is at least 5% by weight of the amount of 6-hydroxy-naphthacene. 7. Process according to any one of claims 1 and 4-6, characterized in that the 6-hydroxy-naphthacene consists of tetracycline and that the 6-deoxy compound formed consists of 6-deoxy-tetracycline. 8. A process according to any one of claims 1 and 3-6, characterized in that the 6-hydroxy-naphthacene is constituted by chlorotetracycline or bromotetracycline and that the 6-deoxy compound formed is 6-deoxytetracycline. 9. Process according to any one of claims 1 and 3-6, characterized in that the 6-hydroxy-naphthacene is 7-chloro-6-demethyltetracycline and that the 6-deoxy compound formed is 6-demethyl-6-deoxytetracycline. 10. A process according to any one of claims 1 and 4-6, characterized in that the 6-hydroxy-naphthaene is derived from 4-epi-tetracycline and that the 6-deoxyphrenate formed is from 6-deoxy-4-epi-tetracycline. 11. A process according to any one of claims 1 and 3-6, characterized in that the 6-hydroxy-naphthacene is 4-epichlorotetracycline or 4-epichromorethracycline and that the 6-deoxy compound formed is 6-deoxy-4- epi-tetracycline. 12. A process according to any one of claims 1 and 3-6, characterized in that the 6-hydroxy-naphthacene is 4-epoxyethracycline and that the 6-deoxy compound formed is 6-deoxy-4-epoxyethracycline. 13. A process according to any one of claims 1 and 4-6, characterized in that the 6-hydroxy-naphthacene is composed of 6-demethyl-4-epi-tetracycline or 7-chloro-6-demethyl-4-epithetracycline and that the formed 6 The deoxy compound is 6-demethyl-6-deoxy-4-epitetracycline. - —7 14. A process according to any one of claims 1 and 4-6, characterized in that the 6-hydroxy-naphthacene is 5-hydroxytetracycline and that the 6-deoxy compound formed is 5-hydroxy-6-deoxy-tetracycline. 15. A process according to any one of claims 1 and 4-6, characterized in that the 6-hydroxy-naphthacene is 6-demethyltetracycline and that the 6-deoxy compound formed is 6-demethyl-6-deoxytetra. 155 551, 158 445. Other publications: Journal of the American chemical society 79 (1957), pp. 4561-63; 80 (1958), pp. 532425.