CH617208A5 - Process for the demethylation of aminoglycoside antibiotics - Google Patents

Description

The invention relates to a process for the preparation of a compound of the general formula

NH

NH

HO

O

CH

HO

OH

wherein R is hydrogen or a methyl group, characterized in that a compound of the following formula

NH

NH

NH

HO

CH

HO

OH

NH

5

10th

15

20th

> 5

30th

35

40

45

50

55

60

65

617208

4th

in which either both Ri and R2 are methyl groups or one of the two Ri and R2 is a methyl group and the other is hydrogen, is reacted with an oxidizing agent,

whereby if both Ri and r2 are methyl groups, the methyl group in the 3 "N position or both methyl groups are eliminated and if one of the two Ri and r2 is a methyl group and the other is hydrogen, the methyl group is eliminated and separation the compound obtained from the reaction mixture.

The following references to the state of the art can be mentioned, in which similar, but not identical, processes for the production of other, constitutionally similar compounds are described.

U.S. Patent No. 3,651,042 (March 21, 1972)

U.S. Patent No. 3,725,385 (April 3, 1973)

• nhch3

15

U.S. Patent No. 3,925,353 (December 9, 1975)

J. Chem. Soc. (c), 1971.3126-3129

Advances in Carbohydrate Chemistry, Volume 17 (1962), pages 214-216

P.N. Rylander, Organic Syntheses with Noble Metal Catalysts,

Academic Press, New York, 1973, pages 113-115

Tetrahedron Lett. 1970.5049-5051

idem 1968, 4085-4086

Tetrahedron 23 (1967), 4691-4696

Chemical Abstracts 77 (1972), 48761

U.S. Patent No. 3,725,385 (April 3, 1973)

J. Chem. Soc. (c) 1971, pages 3126-29

The process according to the invention can be reproduced by the following reaction scheme, compound III corresponding to a starting material or an intermediate product:

Compound I (XK-62-2)

\ Reaction 2

Compound III NH (6'-N-D emethvl- '2 XK-62-2,

Compound II (3 "-N-Q enethy1 - XK-62-2)

Realrti on - 3 \ -ho nh2 oh

/

Compound IV (6'-N, 3 "-N — didemethyl—

XK-62-2)

■ nh ho

Response * 1

nh2 OH

5 617208

The invention is explained in more detail below with reference to the above alkyl chromates, chromyl chloride, selenium dioxide, cobalt (III) salts, reaction schemes. Cerium (IV) salts, potassium hexacyanoferrate (III), copper (II) oxide,

In the demethylation reaction according to the invention, lead oxide, mercury oxide, and mixtures of hydrogen peroxide separate off the partial reactions 1, 2, 3 and 4. The compound I is known as having at least one of the compounds from the group antibiotic XK-62-2 from GB-PS 1 399 578. The s iron (II) salts, iron (III) salts, selenium dioxide, osmium tetroxide, compound I each have, in the 6 'and 3 "position, a methyl vanadate, tungstic acid and chromic acid, lead tetraacetate, amino group Compound I is reacted with an oxidizing agent to produce the chlorine, bromine, iodine, hypochlorates, chlorates, hypobromates, Bro compounds II and IV. Mate, periodates, nitrogen oxide, nitrogen dioxide and air

The compounds II and IV are new, valuable antibiotics. The use of molecular oxygen is preferred. The invention therefore relates to the production of these compounds, as noble metal catalysts used, such as platinum, nickel, fertilize. Palladium, rhodium, ruthenium and rhenium.

The compound II, 3'-N-demethyl-XK-62-2 has a preferred oxidizing agent are chlorine, bromine, iodine, potassium

Antibiotic effect comparable to that of XK-62-2, but umhexacyanoferrate (III), permanganate and air. Particularly lower toxicity than this. The 3 "amino group of the preferred is iodine. In general, 0.5 to 15.0 mol of oxi-bond II can be used with a radioactive methyl group C14H3 detergent per 1 mol of starting compound. When methylated, this results in radioactive XK-62 -2 obtained the use of molecular oxygen or air, which is used for studies on the distribution of XK-62-2, the oxidizing agent in the form of small bubbles through the organism and for metabolic studies of XK- the reaction medium.

62-2 can be used. As a solvent for carrying out the

Compound III is known as gentamicin C] a from US Pat. No. 20 sen, such solvents can be used, 3,091,572. in which the reactants dissolve and those with the

If the compounds II or III are not reacted with an oxidation reactant, or only to a very small extent, the 6'-N or 3 "-N-methyl groups will react. For example, water or mixtures of the respective compound can form the compound IV water with methanol, ethanol, tetrahydrofuran, dimethylace-eliminated. 25 tamide, dimethylformamide, dioxane and ethylene glycol dimethyl

The compound IV, 6'-N, 3 "-N-didemethyl-XK-62-2 can be used in ether.

ner antibiotic effect also comparable to XK-62-2. The starting compounds are preferably in one and also have a lower toxicity than this known concentration of 4.5 to 50 millimolar in the solvent antibiotic. solved.

Compound IV can also be converted into XK-62-2. The reaction according to the invention can be used depending on the type of oxidizing agent used, whereby two radioactive methyl groups (C14H3) can be built at a pH of 4 to 12. This marked connection is valuable to be carried out. The adjustment of the pH value is conveniently achieved by examining the physiological properties of XK-man by adding a corresponding 62-2. Acid or base. Such acids or bases can be used

In the demethylation of compound I into the compounds 35, which neither decompose the starting compounds II and III, reaction I predominates, since the 3 "-N-fertilizers or the demethylated products or a reduction of the ethyl group are easier when the 6'-N-methyl group is eliminated, the oxidizing agent acts, rather an increase is therefore preferred for the preparation of the compound II, preference is given to the action of the oxidizing agent, examples of wise mild reaction conditions are used, while the corresponding inorganic acids are hydrogen chloride production the starting compound III, preferably 40 acid and sulfuric acid, examples of corresponding organically strict reaction conditions can be used, see acids are acetic acid and formic acid, examples of

It should also be noted that in the case of a corresponding base according to the invention, alkali metal hydroxides, alkaline earth metal demethylation of the compound I, a further demethyl metal hydroxide, alkali metal carbonates, alkaline earth metal carbonation of the compounds II and III are unavoidable. This gives nate, alkali metal alkoxides and alkali and alkaline earth metal salts, ie a reaction mixture which generally comprises the compounds of carboxylic acids.

gen II, III and IV contains, albeit also the quantitative ratio. The adjustment of the pH value can be carried out either before the individual compounds react with one another depending on the start of the reaction or during the reaction. As already mentioned, the reaction according to the invention is generally relatively high when the compound II is prey under mild reaction conditions at temperatures of from -20 to 100.degree. C., preferably from 0 to 70.degree. C., while at comparatively severe reaction 50 to 50 hours.

conditions the yield of compound III increases. Finally, the reaction conditions to be used in practice are very high, depending on the type of product desired and the amount of compound IV used, and the oxidizing agent used on compound III is chosen to be as high as possible under very strict reaction conditions. Yields achieved and undesired reactions of other radio

For the preparation of compound IV from compound II via 55 functional groups, such as the hydroxyl and amino groups of reaction 3, relatively strict starting reaction compounds are preferably avoided. The choice of conditions applied, since the elimination of the 6'-N-methyl favorable reaction conditions remains not so easy for the specialist group. man left.

On the other hand, for the preparation of compound IV from, for example, when using iodine, the

Compound III via reaction 4 mild reaction conditions 60 preferred oxidizing agents, sufficient for reaction 1 following. Reaction conditions preferred: 0.7 to 10.0 mol, preferably

To carry out the reaction according to the invention, 2.0 to 6.0 mol of iodine per 1 mol of XK-62-2; Reaction temperatures usual oxidizing agents are used. In particular temperatures from -10 to 90 ° C, preferably 40 to 60 ° C; and can heavy metal salts, peroxides, halogens, oxygen reaction times of 1 to 24 hours, preferably 2 to 15 bonds and oxygen acids of the halogens, nitrogen oxides 65 hours. Furthermore, 0.5 to and molecular oxygen are used to adjust the pH. Examples of 6.0 moles, preferably 2.0 to 4.0 moles of a strong base or suitable oxidizing agents are: permanganates, manganates, 5.0 to 25.0 moles, preferably 7.0 to 15 moles of a weak manganese dioxide, chromic anhydride, Bichromate, chromate, base added.

617208

The following reaction conditions are preferred for carrying out reactions 2, 3 and 4 and for preparing compound IV from compound I: 1 to 13 mol, preferably 5 to 9 mol; 2 to 15 moles, preferably 6 to 11 moles; 0.7 to 10 moles, preferably 2 to 6 moles; or 3 to 15 moles, preferably 7 to 11 moles of iodine per 1 mole of the starting compounds. The remaining reaction conditions are the same as for reaction 1.

After the reaction has ended, the products can be obtained in the customary manner. For example, the reaction mixture is neutralized and concentrated under reduced pressure. The concentrate is placed on a column loaded with a cation exchange resin, on which the unreacted starting compounds and the reaction products are adsorbed, washed with water and then eluted with 2, 1 aqueous ammonia solution. The eluate is generally concentrated and the products are isolated and purified in the customary manner, for example by column chromatography and thin-layer chromatography using ion exchange resins, silica gel, aluminum oxide and cellulose.

Table I shows the acute toxicity (LD 50) values of compounds I, II, III and IV for mice.

Table I

LDso mg / kg

(iv)

Compound I

93

Compound II

200

Compound III

88

Compound IV

138

15

Table II shows the antibacterial spectrum of the compounds I, II, III and IV against various gram-positive and gram-negative bacteria. The minimum inhibitory concentrations are determined by dilution to twice the volume at pH 8.0.

Table II

Tribes

Minimum inhibitory concentration (MIC jig / ml) Verb. Verb. Verb. Verb.

I II III IV

Pseudomonas aeruginosa

1.04

2.08

0.52

0.26

BMH1

Staphylococcus aureus

0.008

0.016

<0.004

<0.004

ATCC6538P

Bacillus subtilis

<0.004

0.008

<0.004

<0.004

No. 10707

Proteus vulgaris

0.065

0.13

0.033

0.033

ATCC6897

Shigella sonnei

0.13

0.13

0.065

0.065

ATCC9290

Salmonella typhosa

0.033

0.065

0.016

0.033

ATCC9992

Klebsiella pneumoniae

0.016

0.033

0.008

<0.004

ATCC10031

Escherichia coli

0.065

0.13

0.033

0.016

ATCC 26

Escherichia coli

8.34

2.08

4.17

4.17

KY 8327

Escherichia coli

1.04

2.08

1.04

1.04

KY 8348

The microorganisms listed in Table II dissolved Escheri- dimethylformamide. 7.3 g (28.8 chia coli KY 8327 and KY 8348 form intracellularly adenyl-so mmol) of iodine are added to the solution and the mixture is transferred under transferase or acetyltransferase for 15 hours. The first mentioned bacterial stirring at 55 ° C implemented. The reactant strain is then inactivated by kanamycins and gentamicins by a mixture of mixtures via adenylation with 150 ml of Amberlite IRC-50 (H + form), while the latter is passed through an acetylene column. The column is inactivated with 600 ml of water. washed. Then 2, On aqueous ammonia

The solution prepared by the process according to the invention is put on. Approximately 250 ml of fractions which may react with ninhydrin compounds in a pharmacologically positive manner are obtained and are converted with acids under reduced, inert, non-toxic salts. Evaporated pressure. 2.60 g of a slightly yellowish example of corresponding acids are inorganic acids, residue. This residue is subjected to column chromatography, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, using 130 g of silica gel with a mixture of sulfuric acid, phosphoric acid and carbonic acid, and also organic isopropanol, chloroform and concentrated aqueous ammoscile acids, such as acetic acid, fumaric acid, malic acid, citric acid solution in the ratio of 4: 1: 1 as eluent, behanic acid, mandelic acid, tartaric acid and ascorbic acid. These salts are delt. The eluate is taken up in fractions of 13 ml volume with acids can be prepared by conventional methods. Fractions Nos 55 to 68 are pooled and the. The examples illustrate the invention. evaporated to dryness under reduced pressure. Man

65 receives 450 mg of unreacted XK-62-2. The fractions Example 1 No. 75 to 83 are also combined and with reduced

2.9 g (6.3 mmol) of XK-62-2 and 9.4 g (69.1 mmol) of sodium acetate pressure were evaporated to dryness. 70 mg of 6-N-trihydrate are obtained in 145 ml of aqueous, 50 percent demethyl-XK-62-2 (compound III, gentamicin cia).

7

617208

F. 113-117 ° C; specific rotation [a] g4 + 171, l ° (c = 0.98, water).

IR spectrum (KBr, cmr1): 3700 to 3000,2940,1630,1575, 1480,1380,1340,1286,1146,1108,1052,1021,957,820.

NMR spectrum (in d2o) S (in ppm against DSS): 1.20 (3H, s), 2.53 (3H, s), 5.13 (1H, d, J = 4.0 Hz), 5 , 23 (1H, d, J = 4.0 Hz) CwHMNSO ^ O: CHN

calc .: 48.81 8.84 14.98

found: 49.36 8.65 14.77

Fractions Nos. 93 to 135 are concentrated under reduced pressure. 1.38 g of 3 "-N-demethyl-XK-62-2 (compound II) are obtained.

F. 105 to 115 ° C; specific rotation: [a] g8 +148.50 (c = 0.097, water).

IR spectrum (KBr, cm-1); 3800 to 3000, 2940, 1640, 1570, 1465, 1379, 1330, 1284, 1142, 110, 1050, 1020, 955, 865, 810; see. Fig. 1.

NMR spectrum (in methanol -di) 5 (in ppm against TMS): 1.16 (3H, s), 2.43 (3H, s), 5.06 (1H, d, J = 3.9 Hz) , 5.20 (1H, d, J = 3.8 Hz); see. Fig. 2.

Cw ^ NsOrHzO: C H N

calc .: 48.81 8.84 14.98

found: 49.36 8.65 14.77

Fractions Nos. 151 to 179 are evaporated to dryness under reduced pressure. 310 mg of 6'-N, 3 "-N-didemethyl-XK-62-2 (compound IV) are obtained.

F. 130 to 140 ° C; specific rotation: [<x] d9 + 97.0 ° (c = 0.10, water).

IR spectrum (KBr, cm-1): 3700 to 3000, 2950, 1630, 1570, 1480, 1380, 1333, 1290, 1149, 1110, 105, 1025, 958; see. Figure 3. NMR spectrum (in d2o) 5 (ppm vs. DSS): 1.18 (3H, s), 5.12 (1H, d, J = 4.0 Hz), 5.29 (IH, d , J = 3.9 Hz); see. Fig. 4. GsH ^ NsOrH-O: C H N

calc .: 47.67 8.67 15.44

found: 47.54 8.39 15.23

Example 2

463 mg (1.0 mmol) of XK-62-2 and 160 mg (4.0 mmol) of sodium hydroxide are dissolved in 25 ml of aqueous 50 percent dimethylacetamide. The solution is dissolved with 659 mg (2.0 mmol) of potassium hexacyanoferrate (III ) offset. The mixture is reacted at 65 ° C. for 15 minutes with stirring. The mixture is then passed through a column charged with 30 ml of Amberlite IRC-50 (H + form). The column is then washed with 150 ml of water. Then 2, on aqueous ammonia solution is put on. About 70 ml of fractions which react positively with ninhydrine are obtained and evaporated under reduced pressure. 430 mg of a slightly yellowish residue are obtained. This residue is worked up by column chromatography using silica gel according to Example 1. 98 mg of unreacted XK-62-2 are obtained. 20 mg of gentamicin Cia (compound III), 210 mg of 3 "-N-demethyl-XK-62-2 (compound II) and 55 mg of 6-N, 3" -N-didemethyl-XK-62-2 ( Compound IV).

Example 3

232 mg (0.5 mmol) of XK-62-2 are dissolved in 15 ml of water. The solution is mixed with 293 mg of fresh platinum black which has previously been activated with hydrogen. The reaction is then carried out for 48 hours, the temperature being kept at 40 to 50 ° C. and a violent stream of fine air bubbles being bubbled through the reaction mixture. When the reaction is complete, the platinum black is filtered off and the filtrate is concentrated under reduced pressure. 211 mg of residue are obtained. This residue is worked up by column chromatography using silica gel according to Example 1. 85 mg of unreacted XK-62-2 are obtained. 17 mg of gentamicin Cia (compound III), 82 mg of 3 "-N-demethyl-XK-62-2 (compound II) and 24 mg of 6-N, 3" -N-didemethyl-XK-62-2 ( Compound IV).

5

Example 4

463 mg (1.0 mmol) of XK-62-2 are dissolved in 25 ml of water. The solution is mixed with 929 mg (5.9 mmol) of potassium permanganate. The mixture is reacted for 17 hours at room temperature 10. The reaction mixture is then passed through a column charged with 30 ml of Amberlite IRC-50 (H + form). After washing the column with 120 ml of water, 2% aqueous ammonia solution is put on. About 80 ml of fractions which react positively with ninhydrin are obtained and 15 are evaporated under reduced pressure. 426 mg of a slightly yellowish residue are obtained. This residue is worked up by column chromatography using silica gel according to Example 1. 110 mg of unreacted XK-62-2 are obtained. Furthermore, 15 mg of gentamicin Cta (compound .20 compound III), 135 mg of 3 "-N-demethyl-XK-62-2 (compound II) and 70 mg of 6'-N, 3" -N-didemethyl-XK are obtained -62-2 (compound IV).

Example 5

; 449 mg (1.0 mmol) 3 "-N-Demethyl-XK-62-2 (Compound II) 25 and 2.04 g (15.0 mmol) sodium acetate trihydrate are dissolved in 30 ml aqueous, 50 percent dioxane. 2.04 g (8.0 mmol) of iodine are added to the solution, and the mixture is reacted for 14 hours with stirring at 60 ° C. The reaction mixture is then charged onto a 30 ml Amberlite IRC-50 (H + -30 form) After washing the column with 150 ml of water, 2% aqueous ammonia solution is put in. About 50 ml of fractions which react positively with ninhydrin are obtained and evaporated under reduced pressure. 420 mg of a slightly yellowish re-35 are obtained This residue is treated by column chromatography using 20 g of silica gel and a mixture of isopropanol, chloroform and concentrated aqueous ammonia solution in a ratio of 4: 1: 1 as the eluent, and the eluate is removed in fractions of 13 ml in volume Fractions No. 37 to 49 are pooled and evaporated to dryness under reduced pressure. 150 mg of unreacted 3 "-N-demethyl-XK-62-2 (compound II) are obtained. Fractions Nos. 61 to 76 are combined and evaporated to dryness under reduced pressure. 45 170 mg of 6'-N are obtained, 3 "-N-didemethyl-XK-62-2 (compound IV).

Example 6

449 mg (1.0 mmol) of 3 "-N-demethyl-XK-62-2 (compound II) and 200 mg (5.0 mmol) of sodium hydroxide are dissolved in 30 ml of aqueous 50% dimethylacetamide. The solution is 824 mg (2.5 mmol) of potassium hexacyanoferrate (III) were added, and the mixture was reacted for 15 hours with stirring at 65 ° C. The reaction mixture was then passed through a column charged with 40 ml of Amberlite IRC-50 (H + form) 55 After washing the column with 140 ml of water, 2% aqueous ammonia solution is put in. About 65 ml of fractions which react positively with ninhydrin are obtained and evaporated under reduced pressure to give 410 mg of a slightly yellowish residue The residue is worked up by column chromatography on acid 60 using silica gel according to Example 5. 220 mg of unreacted 3 "-N-demethyl-XK-62-2 (compound II) are obtained. Furthermore, 110 mg of 6'-N, 3 "-N-didemethyl-XK-62-2 (compound IV) are obtained.

65 Example 7

225 mg (0.5 mmol) of 3 "-N-DemethyI-XK-62-2 (compound II) are dissolved in 20 ml of water. The solution is mixed with 400 mg of fresh platinum black which has been previously activated with hydrogen

617208

8th

that is, offset. The reaction is then carried out for 45 hours, the temperature being kept at 50 to 60 ° C. and a violent stream of fine air bubbles being bubbled through the reaction mixture. When the reaction has ended, the platinum black is filtered off and the filtrate is evaporated under reduced pressure. 195 mg of residue are obtained. This residue is worked up by column chromatography using silica gel according to Example 5. 115 mg of unreacted 3 "-N-demethyl-XK-62-2 (compound II) are obtained. Furthermore, 65 mg of 6'-N, 3" -N-didemethyl-XK-62-2 (compound IV) are obtained.

Example 8

225 mg (0.5 mmol) of 3 "-N-DemethyI-XK-62-2 (Compound II) are dissolved in 110 ml of water. 465 mg (3.0 mmol) of potassium permanganate are added to the solution. The mixture is turned 16 The reaction mixture is then passed through a column charged with 15 ml of Amberlite IRC-50 (H + form). After washing the column with 60 ml of water, 2% aqueous ammonia solution is put on. About 40 ml of fractions, those which react positively with ninhydrin are obtained and evaporated under reduced pressure. 195 mg of a slightly yellowish residue are obtained. This residue is worked up by column chromatography using silica gel according to Example 5. 87 mg of unreacted 3 "-N-demethyl-XK are obtained -62-2 (compound II). 63 mg of 6'-N, 3 "-N-dimethyl-XK-62-2 (compound IV) are also obtained.

Example 9

449 mg (1.0 mmol) 6'-N-demethyl-XK-62-2 (gentamicin C) a, compound III) and 2.04 g (15.0 mmol) sodium acetate trihydrate are dissolved in 40 ml aqueous, 50 percent Dimethylformamide dissolved. 761 mg (3.0 mmol) of iodine are added to the solution. The mixture is reacted at 50 ° C. for 15 hours with stirring. The reaction mixture is then passed through a column charged with 30 ml of Amberlite IRC-50 (H + form). After washing the column with 130 ml of water, 2% aqueous ammonia solution is put on. About 60 ml of fractions which react positively with ninhydrin are obtained and evaporated under reduced pressure. 430 mg of a slightly yellowish residue are obtained. This residue is treated by column chromatography using 20 g of silica gel and a mixture of isopropanol, chloroform and concentrated aqueous ammonia solution in a ratio of 4: 1: 1. The eluate is removed in fractions with a volume of 13 ml. Fractions Nos. 33 to 42 are combined and evaporated to dryness under reduced pressure. 89 mg of unreacted 6'-N-demethyl-XK-62-2 (compound III) are obtained. Fractions Nos. 63 to 85 are combined and evaporated to dryness under reduced pressure. 295 mg of 6'-N, 3 "-N-didemethyl-XK-62-2 (compound IV) are obtained.

Example 10

449 mg (1.0 mmol) of 6'-N-demethyl-XK-62-2 (Gentamicin Cia, compound III) and 160 mg (4.0 mmol) of sodium hydroxide are dissolved in 25 ml of aqueous, 50 percent dimethylacetamide. 659 mg (2.0 mmol) of potassium hexacyanoferrate (III) are added to the solution. The mixture is reacted at 60 ° C. for 15 hours with stirring. The reaction mixture is then passed through a column charged with 30 ml of Amberlite IRC-50 (H + form). After washing the column with 150 ml of water, 2% aqueous ammonia solution is passed over the column. About 80 ml of fractions which react positively with ninhydrin are combined and evaporated under reduced pressure. 415 mg of a slightly yellowish residue are obtained. This residue is worked up by column chromatography using silica gel according to Example 9. 115 mg of unreacted 6-N-demethyl-XK-62-2 (compound III) are obtained. Furthermore, 275 mg of 6'-N, 3 "-N-dide-methyl-XK-62-2 (compound IV) are obtained.

Example 11

225 mg (0.5 mmol) of 6-N-demethyl-XK-62-2 (Gentamicin Cla, compound III) are dissolved in 20 ml of water. The solution is mixed with 400 mg of fresh platinum black which has been previously activated with hydrogen. The reaction is then carried out for 50 hours, the temperature being kept at 40 to 50 ° C. and a violent stream of fine air bubbles being bubbled into the reaction mixture. When the reaction has ended, the platinum black is filtered off and the filtrate is evaporated under reduced pressure. 210 mg of residue are obtained. This residue is worked up by column chromatography using silica gel according to Example 9. 105 mg of unreacted 6'-N-demethyl-XK-62-2 (compound III) are obtained. Furthermore, 87 mg of 6'-N, 3 "-N-dideme-methyl-XK-62-2 (compound IV) are obtained.

Example 12

315 mg (0.75 mmol) of 6-N-demethyl-XK-62-2 (Gentamicin Cia, compound III) are dissolved in 15 ml of water. The solution is mixed with 465 mg (3.0 mmol) of potassium permanganate. The mixture is reacted for 15 hours at room temperature. The reaction mixture is then passed through a column charged with 20 ml of Amberlite IRC-50 (H + form). After washing the column with 80 ml of water, 2% aqueous ammonia solution is added. About 45 ml of fractions which react positively with ninhydrin are combined and evaporated under reduced pressure. 290 mg of a slightly yellowish residue are obtained. This residue is worked up by column chromatography using silica gel according to Example 9. 85 mg of 6-N-demethyl-XK-62-2 (compound III) are obtained. 119 mg of 6'-N, 3 "-didemethyl-XK-62-2 (compound IV) are also obtained.

Example 13

454 mg (1.0 mmol) of 6'-N, 3 "-N-didemethyl-XK-62-2 (compound IV) are dissolved in 4 ml of water. The solution is cooled with a solution of 98 mg (1.0 mmol) of sulfuric acid in 1 ml of water. After 30 minutes, the solution is mixed with cold ethanol until complete precipitation. The white precipitate is filtered off. The monosulfate of 6'-N, 3 "-N-didemethyl-XK is obtained -62-2.

Example 14

4.67 g (10.0 mmol) of 3 "-N-demethyl-XK-62-2 (compound II) are dissolved in 20 ml of water. 1.2 g (20.0 mmol) of glacial acetic acid are added to the solution. After 30 The solution is mixed with cold ethanol until complete precipitation. The white precipitate is filtered off. The diacetate of 3 "-N-demethyl-XK-62-2 is obtained.

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2 sheets of drawings

Claims (7)

617208 1 reacted with an oxidizing agent. 2. The method according to claim 1 for the preparation of 3 "-N-demethyl-XK-62-2 of the formula nh nh (II) nh ho ch ho oh characterized in that XK-62-2 of the formula nhcrl NH nh • nh ho .ho oh nh 2nd PATENT CLAIMS 1. Process for the preparation of a compound of the general formula nk nh nh HO ch ho oh nh wherein R is hydrogen or a methyl group, characterized in that a compound of the following formula nhr nk NH nh HO ch ho OH nh in which either both Ri and R2 are methyl groups or one of the two Ri and R2 is a methyl group and the other is hydrogen, is reacted with an oxidizing agent, where if both Ri and R2 are methyl groups, the methyl group in the 3 "-N-position or both methyl groups are eliminated and if one of the two R 1 and r 2 is a methyl group and the other is hydrogen, the methyl group is eliminated, and the compound obtained is subsequently separated from the reaction mixture. 3rd 617208 characterized in that 3 "-N-demethyl-XK-62-2 of the formula nhck NH (II) NH HO CH HO OH NH2 reacted with an oxidizing agent. 3. The method according to claim 1 for the preparation of 6'-N, 3 "-N-didemethyl-XK-62-2 of the formula nh nh nh • nh ho 0 • CH oh nh2 4. The method according to claim 1 for the preparation of 6'-N, 3 "-Didemethyl-XK-62-2 of the formula NH NH NH 0 NH HO 0 CH OH NH characterized in that one has gentamicin Cla of the formula NH, NH NH 0 NH HO 0 CH HO OH NH reacted with an oxidizing agent. ^ "3 5. The method according to claim 1 for the preparation of 6'-N, 3 "-N-didemethyl-XK-62-2 by reaction of XK-62-2 with an oxidizing agent. 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 6. The method according to claims 1 to 5, characterized in that one carries out the reaction for 0.5 to 50 hours at temperatures from -20 to 100 ° C. 7. Process according to claims 1 to 5, characterized in that iodine, potassium hexaxyano-ferrate (III), air or potassium permanganate is used as the oxidizing agent.