DE2049941C - Process for the production of 2 De carboxamido 2 lminotetracychnes or their acid addition salts or metal salts - Google Patents

Description

CH = NH

OH O OH O
and the formula

CH ₃ N (CH ₃ ),

CH = NH

OH OH O O

wherein R ¹ and P ^{2 are} hydrogen atoms or hydroxyl. R ^{3 is} a hydrogen atom or the

groups

Means methyl group, where R is a methyl group. when R ¹ and R ^{2 represent} hydroxyl groups, R ² and R ³ together can also be the methylene group and R ^{4 is} a hydrogen, chlorine or bromine atom, or their acid addition or metal salts, characterized in that a corresponding 2-decarboxyamidoietracycline Bringing 2-carboxonitrile at a temperature of about -10 to +75 ^C C, preferably at about 40 to 65 "C, with a nickel catalyst and dilute hydrochloric acid or an aqueous solution of a lower alkanoic acid with up to 5 carbon atoms and optionally the obtained Compound converted in a manner known per se with a suitable acid or a suitable metal salt into acid addition salts or metal salts.

2. The method according to claim 1, characterized in that an aqueous alkanoic acid solution with a volume ratio of acid to water of about 1: 5 to 5: 1, preferably about 3: I. is used.

3. The method according to claim I and 2. characterized in that the solution is a lower one Alkanoic acid uses a formic acid solution.

4. The method according to claim 1 to 3, characterized in that that the reaction using 0.1 to 5.0 g. preferably from 0.5 to 2.0 g of nickel catalyst per g of nitrile is carried out.

The invention relates to a process for the preparation of 2 decarboxamido-2-imiiiotetra-

cyclins of the general formula

R- ¹ R 'N (CH ₃ I ₂

IR ³ R ²

i H

OH

OH 0 OH O
and the formula

CH ₃ N (CH-),

/ \ A / VVoH

CH = NH

OH OH O O

where R ¹ and R ^{2 represent} hydrogen atoms or hydroxyl groups, R ^{3 is} a hydrogen atom or a methyl group. where R ^{3 represents} the methyl group when R ¹ and R ^{2 are} hydroxyl groups. R ² around R ³ together can also be the methylene group and R ^{4 is} a hydrogen group. Chlorine or bromine atom is: or their acid addition salts or metal salts, which is characterized by. that a corresponding 2-decarboxamido-tetracycline-2-carboxylic acid nitrile at a temperature of about -10 to +75 C, preferably at about 40 to 65 ° C. with a nickel catalyst and dilute hydrochloric acid or an aqueous solution of a lower alkanecarboxylic acid with up to 5 carbon atoms in order to convert the compound obtained into acid addition salts or metal salts in a manner known per se with a suitable acid or a suitable metal salt.

The tetracycline antibiotics are known to be one Group of biologically active dronaphthacene derivatives with the following structure (Chemical Abstracts, dar:

f-OH

CONH ₂

OH O OH O

So far, the production of tetracyclines ^ was the substituent other than the carboxamiclogruppc in the 2-position contained, mainly limited to tetracyclines, which in the 2-position the cyano, an N-alkylcarboxamido- or contained the acetyl group. Such ine tetracyclines are z. In U.S. Patents 3,028,409, 3,146,264 and 3,226,441. The difficulties in making new and useful 2-substituted tetracyclines with other substituents at the 2-position lay in part in that only a limited number of 2-substituted Tetracycline Vorprocluktcn was available. further in, that the conversion of groups other than those mentioned above into the 2-position of the tetracvcline molecule is difficult.

Surprisingly, it has now been found that Tetracycline-2-carboxylic acids by hydrogenation with a nickel analyzer in dilute hydrochloric acid or can be converted into the corresponding 2-imines in an aqueous alkanoic acid solution, which in turn can easily be converted into other compounds substituted in the 2-position. This process level could not be foreseen in that the tetracycline molecule was a series of functional groups which are attacked by catalytically excited hydrogen, and to change after Journ. Chem. Soc. P. 5881 (1964). the reduction of Nitriles in formic acid solution with Rane nickel in the presence of water leads to aldehydes.

The inventive reaction is at hand, explains the subsequent R 'tion scheme _5:

R ⁴ R ¹ IN (CH ₃ );

'R ³ R ² j;

VVVt-oh

S-. X - ^L CN

OH O OH O

Nickel catalyst in aqueous
Hydrochloric acid or
Carboxylic acid solution

R- R ¹ N ₁ CH ₃ ),

R ³ R ² yy

X / ι L

OH O OH O

VOH

CH = NH

35

40

in which R ¹ , R ² . R ³ and R ^{4 have} the above meaning. In the range from 40 to 65 ° C., the reaction is practically complete in about 15 to 45 minutes.

The ratio of the lower alkanoic acid to water in the aqueous acid solution can be within fairly further limits fluctuate and is not critical for the success of the implementation. Implementation is customary carried out with a volume ratio acid \ u water of about 1: 5 to 5: 1, with a volume ratio from alkanoic acid to water of about 3: 1 is preferred. Particularly advantageous to use are of the lower alkanoic acids with up to 5 carbon atoms, formic acid and acetic acid.

The reduction with the nickel catalyst can also be carried out at room temperature in dilute HCl (0.5 η) or a mixture of methanol and 1 η I ICl (5: 2 V V).

Nickel catalysts vary in their effectiveness in reducing the 2-carboxamido-tctracycline-2-carboxylic acids to (, ₀ the corresponding 2-decarboxamido-tetracycline-2-imines. A catalyst that can be prepared according to Org. Syntheses is preferred Less effective catalysts are not as desirable because they require higher reaction temperatures and / or longer reaction times which tend to degrade the tetracyclines.

The implementation usually takes place in the manner that the tetracyc in-2-carboxylic acid nitrile is added to the stirred aqueous acid solution under nitrogen. Then the nickel catalyst is added and the reaction mixture is heated on a steam bath until the implementation is complete. The catalyst is removed by filtration. Hydrochloric acid will added and the 1min according to the usual methods, z. B. by extraction or conversion into an acid addition salt, isolated.

Generally about 0.1 to 5.0 grams of nickel analyzer will be used per gram of 2-decarboxamidotetracycline-2-carboxonitrile used, with 0.5 to 2.0 g per gram of nitrile being preferred, surprisingly was found here, as already mentioned above, that the tetracyclyi-2-imines resist hydrolysis under the acidic reaction conditions used. Although the reasons for this are not fully understood, it is believed. that the imino group with an enolized, -i-keto group a Forms hydrogen bond and is therefore not subject to hydrolysis.

The 2-decaiboxamidotetracycline-2-carboxylic acid nitrile used as the starting material can be prepared by methods described in J. Chem. Soc., Vol. 75, 5468 (1953): Vol. 79, 2865 (1957): Vol. 77, 1701 (1955) and U.S. Patent 3,069,467. The corresponding tetracycline is then used in Treated with an alkyl or aryl sulfonyl halide in the presence of an organic base. In some Cases in this process is the 10-alkyl or -Arylsulfonyl ester of the corresponding 2-decarboxamidotetracycline-2-carboxylic acid nitrile (cf. J. Am. Chem. Soc., Vol. 77, 1701 [1955]). These esters can be used directly for the hydrogenation described here or they can be used, if desired, by treatment with was .e ^ free hydrofluoric acid into the corresponding tetracycline, which is in the 10-position contains a phenolic hydroxyl group.

It is known that the H ^v droxv! I7ninne S abutment condition of tetracyclines in the presence of acids is very labile at <. Many tetracyclines which contain such a group form the corresponding anhydrotetracycline under acidic conditions (cf. DLJ Clive. Quart. Rev. Vol. 22, 435 [1968]).

This phenomenon also occurs under the acidic conditions of the present process. When therefore the reaction is carried out at higher temperatures, one obtains from the tetracycline-2-carboxylic acid nitrile the 2-decarboxamidoanhydio-tetiacyclin-2-imine. However, routine experimentation can provide suitable conditions to prevent the anhydrous compound from forming. Low Temperatures and short reaction times lead to an imine which has a hydroxyl group in the 6-position contains.

It is also known that the tetracyclines in solution at acidic pH partially convert into their 4-epimers convert. Therefore, the products made according to the invention sometimes contain fractions on 4-epimers. If desired, these can be prepared according to that described in US Pat. No. 3,009,956 Convert process to normal isomer.

The tetracyclines substituted in the 6-position can occur in 2 epimeric forms, namely in the n- and the / (- form. However, this fact has

no significance for the course of the process according to the invention, and the reduction of the second The stereochemistry of the 6-position substituent does not make the nitrile group a 2-position imino group influenced.

The 2-iminotetracyclines of the invention are used for the production of other tetracycline derivatives substituted in! -position, such as 2-formyltetracyclines. of 2-decarboxamidotetracyclinein and 2-aminomethyltetracycline.

A catalytic hydrogenation of the 2-decarboxyamidotetracycline-2-carboxylic acid nitriles in the presence of palladium on carbon does not lead to the formation of the imino group.

The compounds prepared according to the invention have antibacterial activity against various pathogenic microorganisms. which can be determined with the help of standard serial dilution tests. You are to Prevention and reduction e'.ier microbiological Decomposition in various technical petroleum products such as coolants and jet fuels and diesel oils can be used. The antimicrobial effectiveness of the compounds according to the invention makes they are also suitable for use as locally applicable disinfectants, e.g. B. in preparations for treatment of wounds and burns. A typical topical germicidal preparation contains 0.005 to 0.001 percent by weight of the antibiotic, intimately mixed with 10.0 ml of aluminum triacetate solution, 20.0 g of anhydrous lanolin and 30.0 g of incoxide paste. Those produced in the manner according to the invention Compounds can also include soaps and shampoos, ζ. B. liquid hexachlorophene soap. associated ^ t will.

They are also useful as chelating agents and form with many cations, especially with Calcium and magnesium, chelate complexes.

The salts of the new tetracycline compounds' are prepared by conventional methods and are in described in more detail in the examples. Such salts can be used with both pharmaceutically acceptable can also be formed with pharmaceutically incompatible acids and metals. Under »pharmaceutical Compatible ”is understood to mean salt-forming acids and metals that reduce the toxicity of the basic antibiotic do not increase significantly.

The pharmaceutically acceptable acid addition salts are particularly valuable for therapy. For this include salts with mineral acids, such as hydrochloric acid, Hydriodic acid, phosphoric acid. Metaphosphoric acid, nitric acid, and sulfuric acid, as well Salts with organic acids such as tartaric acid, acetic acid, citric acid, malic acid. Benzoic acid. Glycolic acid, gluconic acid. Gulonic acid. Succinic acid and aryl sulfonic acids. such as p-toluenesulfonic acid. If the pharmaceutically incompatible acid addition salts, e.g. B. those with hydrofluoric acid and Perchloric acid, are not suitable for therapy, so they are for the isolation and purification of the new antibiotics useful. The salts with hydrofluoric acid can be prepared by dissolving in hydrochloric acid and crystallization are converted into the pharmaceutically acceptable hydrochlorides.

Many metal salts useful for various purposes can also be prepared. However, the pharmaceutically acceptable metal salts are of particular importance. They include in particular the salts with sodium. Potassium and alkaline earth metals with atomic numbers up to and including 20, ie metal chelates. known in tetracycline chemistry. The pharmaceutically incompatible metal salts mainly include the salts with lithium and with alkaline earth metals with atomic numbers above 20. Λ. H. Barium and strontium, which are useful for isolating and purifying the antibiotics. Since the new antibiotics are amphoteric, they also form salts with sufficiently basic amines.

The following examples explain the process according to the invention.

example 1

30 ml of a 75% formic acid solution were mixed with 2.0 g of 2-decarboxamido-6-deoxy-6-desmethy! Tetracycline-2-carboxonitrile under nitrogen. The mixture was ^be: stirred at room temperature and treated with 2.0 g of Raney nickel was added. Then 45 minutes was stirred on a steam bath, with the temperature rising to about 50 C ^c. The mixture was filtered through diatomaceous earth and the filter cake washed with methanol. 10 ml of 6N hydrochloric acid were added and the fill rat was evaporated to give a greenish foamy residue. Then 15 ml of toluene was added. The mixture was then evaporated under reduced pressure. The addition of toluene and evaporation were repeated in order to ensure complete removal of the formic acid. The green foaming residue was dissolved in 70 ml of n-butanol which was saturated with 1N hydrochloric acid. solved. The n-butanol was added three times with 25 ml of 1N hydrochloric acid each time. which was saturated with n-butanol. extracted. All of the 1N hydrochloric acid extracts were combined and three times with 20 ml of n-butanol each time. which was saturated with 1N hydrochloric acid. extracted. The butanol extracts were combined with the first butanol layer and evaporated. The residue was then treated twice with toluene as described above to ensure complete removal of the butanol. The residue, which consisted of crude yellow, amorphous o-deoxy-o-desmethyltetracyclyl ^ -imine, was dissolved in 15 ml of methanol, converted into the p-toluenesulfonic acid addition salt by adding 2.0 g of p-toluenesulfonic acid and heating the solution on a steam bath. After cooling the solution to room temperature and stirring

Crystals of 2-decarboxamido were obtained overnight - 6 - deoxy - 6 - desmethyltetracyclyl - 2 - imine p-toluenesulfonate. which were filtered off and washed successively with methanol, acetone and ether. the Acis yield was 2.09 g. The same result was obtained when doing the reduction with acetic acid instead of formic acid.

Analysis for C ₂₈ H _1n O ₉ N ₂ S:

Calculated ... C 58.93, H 5.29, N 4.91. S 5.61:
found .... C 58.56, H 5.59, N 4.79. S 5.55.

The analysis sample had a }. _mu% in mn U) of 264 (14 100), 302 (18 600) and 348 (16400) in methanol-0.01 n-HCl.

Example 2

75 ml of a 75% formic acid solution were mixed with 5 g of 7-chloro-2-dccarboxamidoielracveline-2-carboxonitrile at room temperature under nitrogen ver

20th

3 °

networks. This suspension was mixed with 2.5 g of Raney nickel with stirring. Then was stirred for about 20 minutes on a steam bath, the temperature of the reaction mixture reached about 50 ⁰ C. At this point the 7-chloro-2-decarboxamidotetracycline-2-carboxonitrile had completely dissolved. The mixture was stirred for a further 20 minutes at 50 ^° C., cooled to room temperature and filtered through diatomaceous earth. The residue was washed with methanol and the filtrate was diluted with twice the volume of water. 10 g of sulfosalicylic acid were added to the resulting solution. After stirring overnight, the crystallized T-chloro ^ -decarboxamidotetracyclyl-2-imine-sulfosalicylate was filtered off and washed successively with a mixture of methanol and water (1: 1), with acetone and then with ether. The yield was 3.6 g. /. "," In ηΐμ (r) 56 (15,700), 300 (21,800), 340 (10,300) and 371 (14,000) in methanol-0.01 n-HCl.

Analysis for C ₂₉ H ₂₉ O ₁₃ N ₂ SCl • 2H ₂ O
Calculated

C 48.57, H 4.64, N 3.91, S 4.48, Cl 4.94, H ₂ O 5.0; found:

C 48.77, H 4.70, N 3.86, S 4.43, Cl 5.06, H ₂ O 6.4.

Example 3

2.0 g of 2-decarboxamido- a -6-deoxy-5-hydroxy-etracyc-in-2-carbnns; iurenitrile were suspended in 30 ml of a 75% formic acid solution at room temperature under nitrogen. I g of Raney nickel was added and then the reaction mixture was heated on the water bath. When the temperature of the mixture reached 40 ° C, the nitrile was completely dissolved. The mixture was heated for an additional 10 minutes. The reaction temperature was then about 50 ° C. The reaction mixture was stirred and heated for a further 5 minutes until the temperature had reached about 58 ° C. Another 1 g of nickel catalyst was then added and the mixture was stirred for a further 3 minutes Cooled to room temperature and filtered through diatomaceous earth, 2 ml of hydrochloric acid was added and the solution was evaporated under reduced pressure, 30 ml of toluene was added to the greenish foamy residue and the mixture was evaporated again. The toluene treatment was repeated to remove the formic acid completely guarantee.

The residue was dissolved in a mixture of 70 ml of n-butanol (saturated with 1 n-HCl) and 25 ml in HCl (saturated with n-butanol). After shaking the mixture, the n-butanol layer was removed and extracted twice with a small amount of n-HCl (saturated with n-butanol). The HCl extracts were combined and extracted three times with n-butanol (saturated with 1N HCl). The butanol extracts were combined and evaporated and the residue was treated twice with toluene as described above to remove all butanol. The residue had the desired 2-decarboxamido-a-6-deoxy-5-hydroxytetracyclyl-2-imine, a yellow amorphous solid ). _max in πΐμ (e) of 263 (12 900), 300 (15 700) and 350 (14 300) in methanol-0.01 n-HCl.

Example 4 ^6s

Using the procedures of Examples 1-3, the following 2-decarboxamidotetracycline-2-nilrile into the corresponding 2-decarboxamidotetracyclyl-2-imines convicted.

table

R ¹ N (CH ₃ I ₂

OH

35

40

45

55

OH B. O OH O 2 ⁼⁼ R ⁴ R ¹ R ² R ' 2 ⁼⁼ H H H CH., 2 ⁼⁼⁼ Br H OH CH ₃ 2 ~~ Cl H OH H game 5 H H OH H H OH OH CH ₃ H H H CH ₃ Cl H H H H ti CH H OH CH Cl H CH Cl OH CH ice cream

100 ml of a 75% formic acid solution were admixed with 10 g of 2-decarboxamidotetracycline-2-carboxonitrile under nitrogen at room temperature. After stirring the mixture for about 5 minutes. the nitrile had completely dissolved. 10.0 g of a nickel catalyst were added to the resulting solution. The mixture was then heated on a water bath for about 15 minutes, the temperature rising to about 55 ° C. The mixture was then heated to 50-54 ° C for an additional half hour, cooled in an ice bath, and filtered through diatomaceous earth. The residue was washed with a little cold methanol and the filtrate was concentrated to a volume of about 30 ml. About 150 ml of n-butanol (saturated with n-HCl) were then added, and the solution was extracted three times with 50 ml of n-HCl (saturated with n-butanol) each time. The HCl extracts were combined and extracted with n-butanol (saturated with n-HCl). The n-butanol extracts were combined and evaporated to dryness. The yellow-orange crystals obtained were slurried in a small amount of toluene. The mixture was evaporated, methanol was added to the residue and the mixture was kept at room temperature overnight. The 2-decarboxamidoanhydrotetracyclyl-2-imine was filtered off and washed successively with methanol and ether. The yield was 4.89 g. ?. _max in ητ _μ U) 272 (43,000) 298 (20 500), 421 (8 400) in methanol-0.01 n-HCl.

Analysis for C ₂₂ H ₂₃ O ₆ N ₂ Cl ■ H ₂ O:
Calculated:

C 56.83, H 5.42, N 6.02, Cl 7.62, H ₂ O 3.9;
found:
C 5/11, H 5.39, N 6.01, Cl 7.66, H ₂ O 5.2.

If this conversion is carried out at -10 to G "C leads, one receives substantial amounts of the corre sponding 2-decarboxamidotetracyclyl-2-imine.

The hydrochloride acid addition salts of the amphoteric described above Tetracyclines were made by having the Tetracyclines dissolved in methanol containing the iiquimolarc amount of HCl. The Hydrochloric! was then you;; h the addition of ether precipitated by filtration collected and dried. The hydrochloride can be made from. Butanol. Butanol-HCI. Acetone, acetone-HCl or Mcthanol-ΗΓΙ umkristi'.llisicrt '. «earth.

In the same way were with the following acids Acid addition salts produced: sulfuric acid, nitric acid. Perchloric acid. Hydrobromic acid, "Phosphoric acid, hydrofluoric acid, p-toluenesulfonic acid, Hydroiodic acid, tartaric acid, acetic acid, citric acid, malic acid, benzoic acid, glycolic acid. Gulonic acid, gluconic acid, succinic acid, sulfosalicylic acid.

The sodium salts of the tetracyclines described in the preceding examples were prepared by dissolving the amphoteric substance in water. which contained the equimolarc amount of sodium hydroxide, and freeze-drying the resulting mixture c.

In the same way, the potassium and lithium salts manufactured.

The metal salt complexes of the tetracyclines prepared in accordance with the invention were obtained by that the tetracyclines were dissolved in a lower aliphatic alcohol, preferably methanol and with the ik | uimolar amount of the selected metal salt, which is preferably in the selected alcohol was solved, treated. In some cases, the metal salt complexes were obtained by simply filtering them isolated. However, since many of them are soluble in alcohol, they are recovered by evaporation of the solvent or addition of a nonsolvent such as diethyl ether.

In this way, they would work properly manufactured tetracyclines !! and the following metal salts calcium chloride, cobalt chloride, magnesium sulfate, Magnesium chloride, tin (II) chloride, zinc chloride, cadmium chloride. Barium chloride, silver nitrate, Tin (II) nitrate, strontium nitrate, magnesium acetate, manganese acetate, palladium chloride, manganese (II) chloride, Cerium chloride, titanium chloride. Platinum chloride, vanadium ciloid, Blci (II) acetate, tin (II) bromide. Zinc sulphate, chromium (II) chloride and nickel chloride metal salt complexes which contained the metal and the tetracycline mainly in a 1: 1 ratio.

Claims (1)

Patent claims: I. Process for the preparation of 2-decarboxamido-2-iminotetracyclines the general form! R ⁴ R ¹ N (CH ₃ ), R ³ R ²