DK151224B - PROCEDURE FOR PREPARING ALFA-6 DESOXYTETRACYCLINES - Google Patents

Description

151224

The invention relates to a process for catalytic hydrogenation of the exocyclic methylene group in 6-deoxy-6-demethyl-6-methylene tetracyclines with the formula or acid addition salts thereof in claim 1 in an inert solvent in the presence of a complex of rhodium with triphenylphosphine at a temperature of 20 - 100 ° C and at a pressure of 100 atm. under substantially neutral conditions or in the slightly acidic medium produced by the tetra-cyclinic acid addition salt.

U.S. Patent No. 3,200,149 discloses the preparation of 2 15,1224 α-6-deoxytetracycline derivatives by a process involving hydrogenation of certain 6-deoxy-6-demethyl-6-methylenetetracyclines in the presence of a catalytic amount of a precious metal catalyst. , such as rhodium or palladium. In the process, β-6-deoxytetracyclines are produced together with the α-6-deoxytetracyclines.

DE Publication No. 2,308,227 broadly discloses the use of soluble rhodium compounds for stereoselective reduction of 6-deoxy-6-demethyl-6-methylenetetracyclines. However, said disclosure discloses only examples of the use of rhodium (I) compounds. Hui et al., Inorganic Chemistry, 12757 (1973), and the Journal of the Chemical Society (London), Part D, 1195 (1970) report that rhodium (II) diacetate is an effective hydrogenation catalyst. However, the use of rhodium (II) diacetate in the process of the present invention does not lead to a favorable α / β ratio; approximately equal amounts of α- and β-isomers are formed. The presence of the optionally substituted triphenylphosphine ligand is necessary to achieve a stereoselective reduction. Although Legzdins et al. Journal of the Chemical Society (London), Part D, 825 (1969) has reported the use of rhodium diacetate in the presence of triphenylphosphine as hydrogenation catalyst, their experiments were conducted in the presence of a very strong acid. DE Publication No. 2,403,714 discloses a process for hydrogenating the exocyclic methyl group in a 6-methylenetetracycline, wherein the tetracycline compound is treated with hydrogen in the presence of a catalyst consisting of a complex of rhodium and a tertiary phosphine of the formula PR1R2R3 wherein R 1 and R 2 independently represent an optionally substituted phenyl group, wherein the substituent is a halogenatora or an alkyl, alkoxy or dialkylamino group, and R 2 together represents it as or an alkyl or benzyl group, in a solvent medium wherein the tetracycline compound and the catalyst is soluble. By this method, high selectivity for the α-isomers relative to the ε-isomers can be obtained in certain circumstances. However, there are limitations to the solvents that can be used, as it is stated in the specification that at elevated temperatures, dimethylformamide tends to decompose and deactivate the catalyst and that the use of alkanols does not result in as high a stereoselectivity as the use of dimethylformamide . Furthermore, as described, it is desirable to use an acid addition salt of the tetracycline compound as a starting material to obtain a high stereoselectivity.

The process of the invention provides that the hydrogenation of the exocyclic methylene group takes place with a stereoselectivity which favors the Otrisomers relative to the is obtained, whether the acid addition salt or the free base of the tetracycline compound is used as starting material.

The process of the invention is characterized in that the hydrogenation is carried out in the presence of a catalytic amount of a compound of the formula

Rh (OCOR) 2 (P (p6H5J) wherein R is alkyl of 1-6 carbon atoms.

The starting materials of the process of the invention are selected from compounds of the general formula X CH 2 yn (ch 3) 2 COHH 2 OH 0 OH 0 4 151224 wherein X is hydrogen or chloro and Y is hydrogen, hydroxy or alkanoyloxy of 2-7 carbon atoms, or acid addition salts thereof .

The preparation of these starting materials is fully disclosed and illustrated in the specification of U.S. Patent No. 3,200,149. In general, the method of preparation involves treating an 11a-chloro-6,12 hemiketal of the appropriate tetracycline compound with a strong acid of the dehydrating type, such as sulfuric acid, trifluoroacetic acid, polyphosphoric acid, perchloric acid, hydrogen fluoride and the like.

Of these, the preferred acid is hydrogen fluoride. Optimal conditions are easily determined by routine experiments. Generally, the selected 11a chloro metal is simply added to the selected acid and allowed to react, most suitably at a temperature in the range of 0 - 50 ° C and for a period of up to a few hours. After the reaction is complete, the product is recovered appropriately, e.g. in the case of a volatile acid, by evaporation thereof to obtain the product as residue, and in other cases by standard procedures such as stirring with a non-solvent, e.g. diethyl ether, to precipitate the product.

The desired starting material can be prepared by IIa-chlorination of a IIa-chloro-6-deoxy-6-demethyl-6-methylenetetracycline by either chemical or catalytic reduction using procedures well known to those skilled in the art. Example XXXVII in U.S. Patent No. 3,200,149 discloses hydrogenation reduction of an 11a-chloro-6-deoxy-6-demethyl-6-methylenetetracycline hydrochloride to give the corresponding 11a-dichloro compound.

When Y in the starting materials is alkanoyloxy of 2-7 carbon atoms, it is convenient to use the process of the specification of British Patent No. 1,287,493 to prepare them. According to this method, the appropriate 11a-chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline is treated in the form of the free base or a poly-addition salt, with a carboxylic acid having 2-7 carbon atoms in the molecule of presence of methanesulfonic acid, ethanesulfonic acid or hydrogen fluoride acid, preferably at a temperature of 20-70 ° C for a period of generally 2-20 hours. The resulting product can then be reduced to the IIa-dichloro compound by the procedure described above.

These 6-methylene compounds can be converted to acid addition salts or complexes with polyhydric metal salts by standard procedures prior to hydrogenation.

The rhodium compounds of formula Rh (OCOR) 2 (P / CgH, -_ 72) are either known or simple analogous or homologous to known compounds, and the fragments are prepared by such methods as those described by Stephenson et al., Journal of the Chemical Society (London), 3632 (1965). According to these procedures, rhodium carboxylates are prepared by heating hydrated rhodium oxide in e.g. an excess of formic acid, acetic or propionic acid and ethanol under reflux. The yellow solutions gradually turn amber and then green. The resulting solutions are cooled and the precipitated dark green powders are filtered off and recrystallized from methanol or water. These products are found to be stable at temperatures up to 240 ° C. The final catalyst complex is prepared by adding triphenylphosphine or the appropriately substituted triphenylphosphine and diethyl ether to a cold ethanolic solution of the rhodium carboxylate.

Suitable reaction-inert solvents for use in the process of the invention include those which serve to substantially dissolve the starting materials or product. Examples of such solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; lower aliphatic ketones such as acetone and methyl ethyl ketone; low molecular weight esters such as ethyl acetate and butyl acetate; mono- and polyhydric lower alcohols such as methanol, ethanol, isopropanol, ethylene glycol, propylene glycol and diethylene glycol and 2- (2-ethoxyethoxy) ethanol; lower alkanoic acids such as acetic acid and propionic acid; tertiary amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and N-methylpyrrolidone, and mixtures thereof 6

The introduction of hydrogen gas into the reaction-inert solvent containing the rhodium compound and tetracycline is generally accomplished by carrying out the reaction in a closed vessel under an atmosphere of hydrogen or of hydrogen mixed with an inert diluent such as nitrogen or argon. The pressure inside the reaction vessel can vary from 1 to 100 atmospheres. The preferred pressure range when the atmosphere in the reaction vessel is essentially 2 pure hydrogen is 0.7 - 7 kp / cm.

The hydrogenation is generally carried out at a temperature of 20 - 100 ° C, and preferably 40 - 70 ° C. When the preferred temperature and pressure values are used, hydrogenation usually takes place over a few hours, e.g. 2-10 hours. Upon hydrogenation of a 7-halogen-substituted 6-methylene-6-deoxy-6-demethyltetracycline starting material by the process of the invention, the 7-halogen substituent remains essentially intact.

The term "catalytic amount" as used in this specification is well understood by those skilled in the art of the known tetracycline hydrogenations. Generally, this amount is in the range of 0.1-100 mole%, based on the tetracycline substrate. The preferred amount is 1-10 mole%.

The reaction product of the process of the invention can be isolated from the reaction medium by standard methods. Eg. For example, the product can often be precipitated by the addition of a non-solvent such as hexane or water, or by the addition of certain agents which form insoluble salts with the product. Alternatively, the crude product may be isolated by evaporation of the solvent or by diluting the reaction mixture with a large excess of water, followed by extraction of the product in a water-immiscible organic solvent and subsequent evaporation of the solvent.

In the following, the preparation of a known catalyst and the catalyst used according to the invention are illustrated. The following example illustrates the method of the invention and the comparative example illustrates a known method.

PREPARATION OF THE CATALYST A) Rhodium dl) acetate dimer

A mixture of 1.72 g of hydrated rhodium oxide (Rh / OH 7 H 2 O), 6 ml of glacial acetic acid and 15 ml of ethanol is heated at reflux for 24 hours. The reaction mixture is cooled and the volatiles removed by evaporation in vacuo to give the crude product.

The crude product is purified by dissolving in acetone, slowly evaporating the solvent, and filtering off the precipitated solid.

b) Diacetato (triphenylphosphine) rhodium (II)

A mixture of 110 mg of rhodium (II) acetate dimer and 100 ml of methanol is cooled to 17 ° C and a solution of 131 mg of triphenylphosphine in 5 ml of ether is added with stirring. Stirring is continued at room temperature for 2 hours and then the precipitate is recovered by filtration. This gives 219 mg of the above compound, m.p. 203-204 ° C.

EXAMPLE

Reduction of 6-methylene-6-demethyl-6-deoxy-5-hydroxy-tetra-cyclin using diacetatoCtriphenylphosphine) rhodium (II)

A solution of 2.0 g (4.18 mmol) of 6-methylene-6-demethyl-6-deoxy-5-hydroxytetracycline hydrochloride and 0.088 g (4.4 mol%) of diacetato (triphenylphosphine) rhodium (11) in 30 ml of degassed methanol was shaken under an atmosphere of hydrogen in a closed vessel at 60-70 ° C for 3/4 hour. The hydrogen pressure in the reaction vessel was .4.65-5.0 kp / cm 2 man pressure. The vessel was then opened and the reaction solution filtered. The filtrate "was examined by high pressure liquid chromatography which showed that it contained the desired ct-6-deoxy-5-hydroxytetracycline contaminated with 2-3% of its C-6 epimer.

r

To the filtrate was then added a mixture of 20 ml of water and 30 ml of 10% aqueous sulfosalicylic acid with stirring. Stirring was continued overnight and then the precipitate was filtered off to give 2.62 g (95% yield) of oc-6-deoxy-5-hydroxytetracycline as its sulfosalicylate salt. The product was found to be 93% pure by ultraviolet spectroscopy.

COMPARISON EXAMPLE

Reduction of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline using rhodium (II) diacetate

A solution of 2.0 g (4.18 mmol) of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline hydrochloride and 46 mg (5 mol%) of rhodium (ii) diacetate in 30 ml of degassed methanol was shaken under an atmosphere of hydrogen at 65-70 ° C for 5.25 hours. The hydrogen pressure in the reaction vessel was 4.57-4.92 kp / cm pressure. The cooled reaction vessel was then opened and the contents filtered. The filtrate was examined by high-pressure liquid chromatography. This showed that it contained α-6-deoxy-5-hydroxytetracycline and β-6-deoxy-S-hydroxy-tetracycline in a ratio of about 2: 3 together with a small amount of unreduced starting material.

Claims (4)

Tent Requirements: A process of catalytic hydrogenation of the cyclic methylene group in 6-deoxy-6-demethyl-6-methylenetetracyclines of the general formula x ch 2 yn (ch 3) 2 - OH iyOyW-2 OH OH OH wherein X means hydrogen or chlorine, and Y is hydrogen, hydroxy or alkanoyloxy of 2-7 carbon atoms, or acid addition salts thereof in an inert solvent in the presence of a rhodium complex with tripehenylphosphine at a temperature of 20 - 100 ° C and at a pressure of 1 - 100 atm. under substantially neutral conditions or in the slightly acidic medium produced by the tetracyclic acid addition salt, characterized in that the hydrogenation is carried out in the presence of a catalytic amount of a compound of the formula Rh (OCOR) 2 (PZC6H5_73) wherein R is alkyl with 1-6 carbon atoms. Process according to claim 1, characterized in that the reaction temperature is 40 - 70 ° C. Process according to Claim 1 or 2, characterized in that the catalytic amount is 0.1 to 100 mole%, based on the tetracycline compound. Process according to claim 3, characterized in that the catalytic amount is 1 - 10 mol%, based on the tetracycline compound.