DE2049941B - Process for the preparation of 2-decarboxamido-2-iminotetracyclines, or their acid addition salts or metal salts - Google Patents

Description

OH O OH O

and the formula

CH ₃ N (CH ₃ ),

CH = NH

OH OH O O

cyclins of the general formula

R * R ¹ N (CH ₃ ^
^J

where R ¹ and R ^{2 are} hydrogen atoms or hydroxyl groups, R ^{3 is} a hydrogen atom or the methyl group, where R ^{3 is} a methyl group when R 'and R ^{2 represent} hydroxyl groups, R ² and R ³ together can also be the methylene group and R ⁴ a hydrogen, chlorine or bromine atom, or their acid addition or metal salts, characterized in that a corresponding 2-Decarboxyamidotetracyclin-2-carbonitrile at a temperature of about -10 to +75 ⁰ C, preferably at about 40 to 65 ° to C, brings into contact 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 converts the compound obtained 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 there is an aqueous alkanoic acid solution with a volume ratio of acid to water of about 1: 5 to 5: 1, preferably about 3: 1, used.

3. The method according to claim 1 and 2, characterized in that there is a solution as a lower Alkanoic acid uses a formic acid solution.

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

OHOH O

where R ¹ and R ^{2 represent} hydrogen atoms or hydroxyl groups, R ^{3 is} a hydrogen atom or the methyl group, where R ^{3 represents} the methyl group when R ¹ and R ^{2 are} 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 its acid addition salts or metal salts, which is characterized in that a corresponding 2-decarboxamido-tetracycline-2-carboxonitrile 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 and optionally the compound obtained in a known manner with a suitable acid or a suitable metal salt in acid addition salts or Metal salts transferred.

The tetracycline antibiotics are known to represent a group of biologically active hydronaphthacene derivatives with the following framework (Chemical Abstracts):

CONH ₂

OH O OH O

The invention relates to a process for the [preparation of 2-decarboxamido-2-iminotetra-so far was the preparation of tetracyclines that have other substituents than the carboxamido group 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 tetracyclines are z. B. 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 that only a limited number of 2-substituted tetracycline precursors were available; that the introduction of groups other than those mentioned above into the 2-position of the tetracycline molecule is difficult.

049 341

Surprisingly, it has now been found that tetracycline-2-carboxylic acid nitride by hydrogenation with a nickel catalyst in dilute hydrochloric acid or in an aqueous alkanoic acid solution in the corresponding 2-imines can be converted to the again easily substituted into others in the 2-position Connections are transferable. This course of the procedure could not be foreseen insofar as it was once the tetracycline molecule has a number of functional groups created by catalytically excited hydrogen are attacked, and on the other hand after Journ. Chem. Soc, S. S881 (1964), the reduction of Nitriles in formic acid solution with Raney nickel in the presence of water leads to aldehydes.

The reaction according to the invention is explained using the following reaction scheme:

R '

OH

CN

OH O OH O

Nickel catalyst in aqueous
Hydrochloric acid or
., Carboxylic acid solution

R ¹ N (CH ₃ J ₂

OH O OH O

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 essential to the success of the Implementation not critical. The reaction is usually carried out with an acid to water volume ratio from 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 n) or a mixture of methanol and 1 η HCl (5: 2 V / V).

Nickel catalysts vary in the reduction of the 2-decarboxamido-tetracycline-2-carboxonitrile too the corresponding 2-decarboxamidotetracycline-2-imines in their effectiveness. A catalyst that according to Org. Syntheses, anthology 3, 181 (1955), producible is is preferred. Less effective catalysts are not as desirable as they are higher Require reaction temperatures and / or longer reaction times, which are easy to break down Lead tetracyclines.

The 'reaction is usually carried out in such a way that the tetracycline ^ -carbonsäurenitril under Nitrogen is added to the stirred aqueous acid solution. Then the nickel catalyst is added and that The reaction mixture is heated on a steam bath until the reaction is complete. The catalyst becomes removed by filtration, hydrochloric acid becomes added and the imine by customary methods, e.g. by extraction or conversion into a

ία acid addition salt, isolated

Generally about 0.1 to 5.0 grams of nickel catalyst per gram of 2-decarboxamidotetracycline-2-carboxonitrile will be used is used, with 0.5 to 2.0 grams per gram of Nilril being preferred. Surprisingly was found here, as already mentioned above, that the Tetracyßlyl-2'imine among the applied withstand acidic reaction conditions of hydrolysis. Although the reasons for this are not yet complete are clarified, it is assumed that the imino group with an enolized ^ -Keto group a Forms hydrogen bond and is therefore not subject to hydrolysis.

The 2-decarboxamidotetracycline-2-carboxylic acid nitrile used as the starting material can be prepared by methods described in J. Cheai. Soc., Vol. 75, 5468 (1953); Vol. 79, 2865 (1957); Vol. 77, 1701 (1955) and in U.S. Patent 3069467 are. Thereafter, the corresponding tetracycline is in the presence of an organic base with an alkyl or arylsulfonyl halide treated. In some cases, this method uses the 10-alkyl or -Arylsulfonyl ester of the corresponding 2-decarboxamidotetracycline-2-carboxylic acid nitrile obtained (cf. J. Am. Chem. Soc, Vol. 77, 1701 [1955]>. These esters can be used directly for the hydrogenation described herein, or they can if desired by treatment with anhydrous hydrofluoric acid into the corresponding tetracycline, which is in the 10-position contains a phenolic hydroxyl group.

It is known that the hydroxyl group is in the 6-position the tetracyclines are very labile in the presence of acids. Many tetracyclines that are one such group contain, form the corresponding Anhydrotetracyclüi under acidic conditions (cf. D. L. J. 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, is obtained from the tetracycline-2-carboxylic acid nitrile the 2-decarboxamidoanhydrotetracycline-2-imine. With routine experiments you can however, establish suitable conditions which prevent the formation of the anhydro compound. 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 carried out according to that described in US Pat. No. 3009956 Process into the normal isomer

6s convert.

The tetracyclines substituted in the 6-position can occur in 2 epimeric forms, namely in the α- and the ß-Fona. However, this fact has

for the course of the method according to the invention is of no importance, and the reduction of the ^ permanent Nitrügroppe to the 2nd imino influenza is through the stereocbcmic of the permanent substituent is not influenced.

The 2-IminotetracycUne according to the invention are used for the production of other tetracycline derivatives substituted in the 2-position, such as 2-formyl tetracydines, of 2-dycarboxainidoietracyclines and 2-aminomethyltetracyclines.

A catalytic hydrogenation of the 2-decarboxyamidotctracycün-2-carboxylic acid nitrile 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 of microbiological decomposition in various technical petroleum products, such as coolants, jet fuels and diesel oils. The antimicrobial effectiveness of the compounds of the invention also renders them 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 anhydrous lanolin and 30.0 g zinc oxide paste. Those produced in the manner according to the invention Compounds can also include soaps and shampoos, ζ. B. liquid hexachlorophene soap added 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 as 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 ones are of particular importance Metal salts. They include in particular the salts with sodium, potassium and with eidalkali metals Atomic numbers up to and including 20, dk metal chelates, which are known in the tetracycline end. To the Pharmaceutically incompatible metal salts mainly include the salts with lithium and with alkaline earth metals with breath counts above 20, i.e. barium and strontium, which are used for isolation and purification the antibiotics usable and. Since the new Antibiotics are amphoteric, they also form salts with, o 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-desmethyltetracycün-2-carbon ^ urenitrile under nitrogen The mixture was stirred at room temperature, and 2.0 g of Raney nickel were added. Then became

ίο stirred for 45 minutes on a steam bath, with the temperature rising to about 50 ⁰ 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 filtrate 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. The n-butanol was extracted three times with 25 ml each time of 1N hydrochloric acid saturated with n-butanol. All of the 1N hydrochloric acid extracts were combined and three times with 20 ml each time of n-butanol saturated with 1N hydrochloric acid was extracted. The butanol extracts were combined with the first butanol layer and evaporated. The residue was then treated twice with toluene as described above in order to ensure the complete removal of the butanol. The residue, which consists of crude yellow, amorphous o-deoxy-o-desmethyltetracyclyW-imine

was by dissolving in 15 ml of methanol, adding 2.0 g of p-toluenesulfonic acid and heating the solution on a steam bath into the p-toluenesulfonic acid addition salt converted. After cooling the solution to room temperature and stirring overnight crystals of 2-decarboxamido - 6 - deoxy - 6 - desmethyltetracyclyl - 2 - iminp-toluenesulfonate, which were filtered off and washed successively with methanol, acetone and ether. the 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 ₃₀ O ₉ N ₂ S:

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

The analysis sample had an X _n ^ in ηΐμ (e) of 264 (14100), 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-decarboxamidotetracycline-2-carboxylic acid nitrile at room temperature under nitrogen ver

puts. 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 7-chloro-2-decarboxamidotetracyclyl-2-imine-sulfosalicylate was filtered off and washed successively with a mixture of methanol and water (i: i), with acetone and then with ether. The yield was 3.6 g. λ _ηαχ in πΐμ ( _f ) 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-α-6-deoxy-5-hydroxytetracycline-2-carboxylic acid nitrile were suspended in 30 ml of a 75% formic acid solution at room temperature under nitrogen. 1 g of Raney nickel was added and then the reaction mixture was heated on the water bath. When the temperature of the mixture had reached 40 ⁰ C, the nitrile was completely dissolved. The mixture was heated for an additional 10 minutes. Thereafter, the reaction temperature was about 50 ⁰ C. The reaction mixture was stirred for a further 5 minutes, and heated until the temperature was about 58 ° C reached. Another 1 g of nickel catalyst was then added and the mixture was stirred for a further 3 minutes. It was then cooled to room temperature and filtered through diatomaceous earth. 2 ml of hydrochloric acid was added and the solution was evaporated under reduced pressure. The greenish foaming residue was admixed with 30 ml of toluene and the mixture was evaporated again. The toluene treatment was repeated to ensure complete removal of the formic acid.

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-HQ (saturated nrit n-butanol). The HQ extracts were combined and extracted three times with n-butanol (saturated with 1 n-HQ). The butanol extracts were combined and evaporated and the residue was treated twice with toluene as described above to remove all butanol. The residue, the desired 2-decartx> xamido-a-6-deoxy-S-hydroxytetracyclyl ^ -nnin, a yellow amorphous solid, had ί _M "inmμ W of 263 (12 900), 300 (15 700) and 350 ( 14 300) in methanol-0.01 n-HCL

Example 4

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

R ⁴

table

R ¹ N (CH ₃ J ₂

OH O OH O R * 15 ^R1 R ² R ³ H H H CH ₃ Br H OH CH ₃ Cl H OH H H 20 _H. OH H H OH OH CH ₃ H H H CH ₃ Cl H H H H ² 5 H. CHj = H OH CHj = Cl H CH ₂ = Cl OH CHj =

^3U example 5

100 ml of a 75% formic acid solution were mixed with 10 g of 2-decarboxamidotetracycline-2-carboxonitrile under nitrogen at room temperature offset.

After stirring the mixture for about 5 minutes, the nitride had completely dissolved. 10.0 g of a nickel catalyst were added to the resulting solution. Then it was about 15 minutes heated on a water bath, the temperature rising to about 55 ° C. The mixture then became a heated to 50 to 54 ° C for another half hour, cooled in an ice bath and filtered through diatomaceous earth. The residue was washed with a little cold methanol and the filtrate to a volume of about 30 ml concentrated. Then about 150 ml of n-butanol (saturated with n-HCl) was added and the solution became extracted three times with 50 ml of n-HCl (saturated with n-butanol) each time. The HO extracts were combined and extracted with n-butanol (saturated with n-HCl).

The n-butanol extracts were combined and zui Evaporated to dryness. The obtained yellow-orange crystals were dissolved in a small amount of toluene slurried. The mixture was evaporated, methanol was added to the residue and the mixture was left to stand overnight.

Kept room temperature. The 2-decarboxamidoanhydrotetracyclyl-2-imine was filtered off and washed successively with methanol and ether. The yield was 4.89 g. υ «« in ταμ (e) 272 (43,000] 298 (20,500), 421 (8,400) in methanol-0.01 n-HCS.

Analysis for C ₂₂ H ₂₃ O ₆ N ₂ Q - H ₂ O:

Calculated:
C 56.83, H 5.42, N 6.02, Q 7.62, H ₂ O 3.9;

found:
C 57.11, H 53, N 6.01, Q 7.66, H ₂ O 5.2.

If this reaction at -10 leads to 0 ⁰ C Runaway, we obtain substantial amounts of entspn sponding 2-Decarboxamidotetracyclyl-2-imine.

* ma coo / c-

The hydrochloride acid addition salts of the amphoteric described in the previous examples Tetracyclines were prepared by dissolving the tetracyclines in methanol, which is the equimolar Amount of HCl contained. The hydrochloride was then precipitated by the addition of ether, by filtration collected and dried. The hydrochloride can be selected from butanol, butanol-HCl, acetone, acetone-HCl or methanol-HCl can be recrystallized.

Acid addition salts were prepared in the same way with the following acids: sulfuric acid, nitric acid, Perchloric acid, hydrobromic acid, phosphoric acid, hydrofluoric acid, p-toluenesulfonic acid, Hydriodic 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 previous examples were prepared by dissolving the amphoteric substance in water containing the equimolar amount of sodium hydroxide, and freeze-dried the resulting mixture.

The potassium and lithium salts were prepared in the same way.

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 equimolar 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 the addition of a nonsolvent such as diethyl ether.

In this way, with the tetracyclines prepared according to the invention 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 chloride, lead (II) acetate, tin (II) bromide, zinc sulfate Chromium (II) chloride and nickel (II) chloride metal salt complexes are made that contain the metal and the tetra cyclin mainly in a 1: 1 ratio.

Claims (1)

Patent claims: 1. Process for the preparation of 2-decarboxamido-2-iminotetracyclines of the general form mel R ⁴ R ¹ N (CHa) ₂ R ³ R ² IO