FI67210B - FRAME STARTER FOR ALFA-6-DEOXY-TETRACYKLIN - Google Patents

Description

! 67210

The present invention relates to a new selective process for the preparation of o-6-deoxy-tetracycline of the formula -I-6-deoxy-tetracycline of the formula I-CH-OH N (CHO) -i JH i H i 3 2 'I' ^ ^ lu)

Sy / ^ CONH 2

OH O OH OH O

and acid addition salts thereof by a process

according to 6-methylene-5-hydroxy-tetracycline-by, formula II

is OH N (CH 2), CH 2 H; H! 32 ^ \> As ^ As! / A> ^ oh S \ / ^ 'c0NH2

OH O OH 0H O

or a corresponding 11a-chloro derivative thereof, or an acid addition salt thereof, is hydrogenated in the presence of a palladium catalyst in a solvent, the process of which is characterized in that the reaction mixture contains a palladium complex compound of diphenylselenide.

The compound of formula I to be prepared according to the invention is a known broad-spectrum and long-acting antibiotic.

The preparation of o (-6-deoxy-tetracyclines) has been previously described in FI patent publication 43,313. , for example in an aqueous solvent, the reaction then produces more Of-6-deoxy-tetracycline than β-6-tetracycline compared to the previously known hydrogenation method using a non-toxic catalyst. several other sulfur compounds have been mentioned which have a beneficial effect on the ability of the catalyst to produce the isomer The polar organic solvents and their aqueous solutions are suitable as the solvent.

When studying the effects of complex compounds on the ability of a palladium catalyst to produce cis-isomers of 6-deoxy-tetracyclines, it has surprisingly been found that guiding effect. Unlike some other precious metal complexes, the diphenylselenide complex used alone is not reducible.

The ratio of the α- and β-isomers formed in the reaction depends essentially on the ratio of the palladium catalyst to the complex compound. When optimal amounts of complex compound are used, the cf isomer is selectively formed in the reaction mixture. The optimal diphenylselenide complex / palladium catalyst ratio depends on the solvent system used and must therefore be determined separately for each solvent system used. Particularly good results have been obtained when the palladium catalyst is 5% palladium carbon and the complex compound is bis (diphenylselenide) palladium (II) chloride. By way of example, when a solvent mixture containing 40% by volume of water in methanol is used, the optimum ratio of palladium complex to catalyst is 6 to 10 mg of palladium complex compound per 100 mg of palladium on carbon catalyst.

Particularly good results are obtained when the solvent contains small amounts of a strong mineral acid such as hydrochloric acid or formic acid.

On the other hand, when more than the optimal amount of the complex compound is used, almost no β-isomer is formed, but instead residues of the compound of formula II may be present in the reaction product from which the c (-isomer) can be easily isolated.

The orienting effect described above is best achieved in polar solvents such as methanol or aqueous organic solvents. The preferred hydrogenation temperature is about 15 to 40 ° C with a slight overpressure of hydrogen up to 150 kg / cm 2.

The reaction time depends on the amount of complex compound used, the acidity of the solution, the pressure and the quality of the palladium catalyst, ranging from a few hours to 12 hours.

On the other hand, when studying the effect of non-complex diphenylselenide on the properties of noble metal catalysts under the reaction conditions described above, it has been found that small amounts of this compound increase the proportion of o (-isomers) in the reaction mixture, for example without using the prior art described above. By increasing the amount of diphenylselenide in the reaction mixture, the catalyst eventually loses its reducing power completely without the formation of the <X isomer in the reaction mixture becoming selective.

467210 tf-6-deoxy-tetracycline is isolated from the reaction mixture in a manner known per se, e.g. by precipitation as the 5-sulfosalicylate salt.

The diphenylselenide complex can be prepared by dissolving the palladium chloride in question in methanol, to which is added. the amount of diphenylselenide purified with activated carbon depending on the coordination number of the metal. The complex compound precipitates from solution as the solution is concentrated and cooled.

The invention is illustrated by the following example:

Example A. Preparation of bis (diphenylselenide) palladium (II) chloride 17.7 mg of palladium (II) chloride was weighed into a solution containing 46.6 mg of diphenylselenide in 20 ml of methanol.

The mixture was stirred at 40 ° C until the palladium chloride was dissolved. The solution was concentrated to a volume of 10 mL, cooled and filtered. Yield 40.5 mg of the brick red crystalline title compound.

B. Preparation of c (-6-deoxy-tetracycline) 3.0 mg of bis (diphenylselenide) palladium (II) chloride was dissolved in a solution of 10 ml of water and 15 ml of methanol in a 250 ml autoclave. To the resulting yellowish solution was added 0.25 g concentrated hydrochloric acid and 50 mg of palladium on carbon (5%) and the suspension were stirred for 15 min, 0.6 g of 6-methylene-5-hydroxy-tetracycline hydrochloride was added to the autoclave and the mixture was hydrogenated at room temperature for 10 hours with stirring at 25 kg / cm To the filtered reaction mixture (5 67210) was added 5 ml of water and the reaction mixture was mixed as a sulfosalicylate salt, with a total yield of about 0.65 g, of which the oi isomer content was about 95%. ethyl acetate: nitromethane: chloroform 40: 15: 4 Development with ammonia gas.

Claims (3)

6,67210 A process for the preparation of o (-6-deoxy-tetracycline of the formula CH 3 OH N (CH 3) 2 CONH 2 OH 0 OH 0 H 0 and its acid addition salts, which process comprises 6-methylene-5-hydroxy-tetracycline of the formula OH N ( A process according to claim 1, characterized in that the reaction mixture contains a palladium complex of diphenylselenide. that the diphenylselenide dipalladium complex compound is bis (diphenylselenide) palladium (II) chloride. Process according to Claim 1 or 2, characterized in that the palladium catalyst is palladium carbon.