KR790001140B1 - Process for the preparation of antibiotics - Google Patents

Abstract

The title compd. (B; n = 1-4) with strong antibacterial activity was prepd. by reaction of antibietics(A) with antioxidant at -20- 100≰C, PH 4.0-12.0 for 0.5-50 hrs. and then isolation and purification by column chromatography or TLC method.

Description

Method for preparing derivatives of antibiotics

The present invention relates to a method for producing mycobacterial antibiotic derivatives (hereinafter referred to as (1) substance) represented by Structural Formula (B).

N is an integer of 1-4.

In more detail, the present invention is characterized by removing the methyl group of the N-methyl group at the 3'-position by reacting the antibiotic derivatives represented by Structural Formula (A) (hereinafter referred to as (2) substance) with an oxidizing agent. The present invention relates to a method for producing new antibiotic derivatives represented by Structural Formula (1).

N is as described above.

In the present invention, the material (1) includes the following compounds.

Namely, the substance (1) when n is 1 is 3 "-N-dimethyl-1- [α-hydroxy-β-aminopropionyl] XK-62-2,

(n) when n is 2, the substance is 3 "-N-demethyl-1- [L-(-)-α-hydroxy- γ-aminobutyl] XK-62-2,

(n) when n is 3, the substance is 3 "-N-demethyl-1- [L-(-)-α-hydroxy- δ-aminobareryl] XK-62-2,

The substance (1) when n is 4 is 3 "-N-demethyl-1- [L-(-)-α-hydroxy-ε-amino caproyl] XK-62-2.

The substance (1) aimed at by this invention is an entirely new compound for which the use as an antibiotic substance with strong antibacterial activity is anticipated.

Hereinafter, the present invention will be described in detail.

In the present invention, (1) the substance is prepared by reacting (2) the substance with an oxidizing agent in a ball-active solvent to remove the methyl group of the N-methyl group in the 3 "-position.

The material (2) which is the raw material compound of the present invention is an amino group of position 1 of the antibiotic XK-62-2 filed by the present applicant (see Patent Publication No. 49-13391), which is represented by [] in the following table (I). It is prepared by acylating with each acyl group.

TABLE I

In the present invention, the oxidation method can produce the substance (1) by oxidizing the substance and the oxidizing agent in a suitable inert solvent under the following conditions. The reaction temperature is carried out within the range of -20 ° -100 ° C (generally 0 ° -70 ° C). The reaction time is performed in the range of 0.5-50 hours, and the pH of the reaction solution is performed in the range of 4.0-12.0.

Reconditioning of these reactions is appropriately selected within the above range depending on the type of oxidant, the amount of use and the reaction conditions thereof.

As an oxidizing agent used in this reaction, it means a general oxidizing agent and a compound having potential oxidizing power. Specific examples thereof include various heavy metal salts, peroxides, halogens, halooxygen acids, nitrogen oxides, and precious metals. More specifically, for example, permanganate, manganate, manganese dioxide, chromic anhydride, dichromate, chromate, alkyl chromium chloride, chromyl chloride, selenium dioxide, second cobalt salt, second cerium salt, red blood One or more compounds selected from salts, copper oxides, lead oxides, mercury oxides, hydrogen peroxide and the following reagents: ferrous salts, ferric salts, selenium dioxide, osmium chloride, vanadates, tungstic acid, chromic acid, lead tetraacetate Anti-oxidants such as chlorine, clear, iodine, hypochlorous acid, chloric acid, hypochlorous acid, cancelled acid, periodic volcano, nitrogen dioxide, nitrogen monoxide and nitrogen dioxide, platinum, nickle, palladium, osmium, ruthenium, rhenium Noble metals.

Although the present invention may use any of the above oxidizing agents, preferred are chlorine, cancellation, iodine, erythritis, permanganate, platinum (most preferably iodine), and the like. (2) The substance has functional groups such as hydroxyl group and amino group in its molecule, but in the reaction with the general oxidant, the amount of the oxidant, the acidity of the reaction solution, the reaction temperature, the reaction time, and the solvent amount are appropriately adjusted and these functional groups are used. It is possible to achieve the object of the present invention and avoid significant loss of. In addition, when using a noble metal as an oxidizing agent, the thing immediately after activating is used, and it is good to carry out in air or oxygen presence.

The amount of the oxidizing agent to be used may be 0.5-15.0 moles per mole of the starting compound, but may be appropriately selected from the above ranges depending on the type of relaxant, the reaction temperature, and the reaction conditions thereof.

As the solvent used in the present invention, a solvent which dissolves the reaction reagents and does not react with them to a significant extent may be used.

Examples of the solvent used may include water alone or a mixed solvent of water with one or more mixed solvents selected from methanol, ethanol, tetrahydrofuran, dimethylacetamide, dimethylformamide, dioxane, ethylene glycol dimethyl ether, and the like. have.

When carrying out the present invention, the reaction conditions are carried out as follows using a better iodine. (2) The urea used to remove the methyl group of the N-methyl group in the 3 "-position of the material (1) to produce the material in good yield (2) 0.7-10.0 moles per mole of material (2.0-6.0 moles is preferred) Range.

In the case of using urea as an oxidizing agent, when the pH of the reaction solution is made basic, the target compound can be obtained in good yield. The conditions as basic substances used to make the pH of the reaction solution basic in the reaction are (2) less likely to react with and decompose the substances and demethylated products, and react with the iodine to substantially reduce the reactivity of the iodine. Examples thereof include alkali metals, hydroxides and carbonates of alkali metals, alcoholic side of alkali metals, alkali metal salts of carboxylic acids and alkali earth metal salts of carboxylic acids that do not decrease. The amount of the basic substance used is 0.5-0.6 mol (1.5-3.5 mol) of the substance (2) in the case of a strong basic substance. In addition, in the case of a weakly basic substance, it is 5.0-25.0 mol (5.0-13.0 mol is preferable). These basic substances are not intrinsically different even if added at the start of the reaction or appropriately added during the reaction.

The reaction temperature is generally in the range of -10-90 ° C (preferably in the range of 20-50 ° C), and the reaction time required for terminating the reaction is 1-24 hours (generally 2-15 hours).

In the method of the present invention, (1) only a substance is produced very rarely, and (1) the substance and (2) a compound in which the methyl group of the N-methyl group at the 6'-position of the substance is released [hereinafter (3) substance And (2) a compound in which the methyl group of the N-methyl group at the 6'-position and the 3 "-position of the substance is released at the same time (hereinafter referred to as (4) substance).

Isolation and purification of the product from the reaction solution may be performed by the following method.

After neutralizing the reaction solution or concentrated under reduced pressure, an aqueous solution of the residue was brought into contact with a cation exchange resin to deposit unreacted raw materials and products, washed with water and eluted with 2.0 N ammonia water. After concentration, it is isolated and purified by known isolation and purification methods, for example, column chromatography or TLC method using an adsorbent such as ion exchange resin, silica gel, alumina, cellulose and the like. The substance (1), which is the target compound of the present invention, is a novel antibiotic derivative, and is a compound useful as an antibiotic since it has intrinsic antibacterial activity.

3 "-N-demethyl-1- [L-(-)-α-hydroxy-γ, which is one of the target compounds of the present application, for the various types of Gram-positive bacteria and negative bacteria obtained by the 2-fold dilution method in Table (1). -Aminobutyl] The antibacterial spectrum of XK-62-2 is shown.

TABLE 1

In the above table, E. coli KY 8327 and KY 8348 produce adenylase and acetylase in cells, respectively, the former adenylated kanamycin and gentamycin, and the latter acetylated gentamycin to inactivate antibiotics. It is a bacterium.

The substance (1) which is the target compound of the present invention can be made of non-toxic acid and addition salts (that is, betel salts) if necessary. Here, non-toxic acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and carbonic acid, and organic acids such as acetic acid, fumaric acid, malic acid, citric acid, mandelic acid, tartaric acid and ascorbic acid, The manufacturing method of addition salt with the said acid is known.

In the following examples, the present invention will be described in detail, but various modifications are possible, and these are not limitative of the present invention.

Example 1

720 mg (1.28 mM) of 1- [L-(-)-α-hydroxy-γ-aminobutyl] -XK-62-2 (hereinafter referred to as Compound II) and 2.10 g (15.4 mM) of sodium acetate 3H ₂ O It is dissolved in 55.0 ml of 50% dimethylformamide, 1.8 g (7.1 mM) of iodine is added thereto, and the reaction is carried out at 55 ° C. for 2.5 hours under stirring. The reaction solution was passed through a column with 50 ml of Amberlite (Rohm & Haas) IRC -50 (H ⁺ type), followed by washing with 200 ml of water. Nearly 85 ml of the color developed with drin is driven and concentrated under reduced pressure to yield 670 mg of a nearly yellow residue. This residue was subjected to column chromatography using a solvent of isopropanol: chloroform: concentrated ammonia water = 4: 1: 1 using 25 g of silica gel. The effluent was taken in 12 ml portions and the fraction No. Drive 35-55, concentrate under reduced pressure, and dry to recover 210 mg of unreacted compound II.

If you continue, the fraction No. 61-69 was concentrated to dryness under reduced pressure to give 54 mg of 6'-N-dimethyl-1- [L-(-)-α-hydroxy-γ-aminobutyl] XK-62-2 (hereinafter referred to as compound II). .

In addition, fraction No. 73-101 was concentrated under reduced pressure to afford 3 "-N-demethyl-1- [L-(-)-α-hydroxy-γ-aminobutyl] XK-62-2 (target compound of the present application) 175 mg was obtained.

Infrared Absorption Spectrum ν _c = 0.1640cm ^-1

NMR Spectrum (ppm at TMS in heavy methanol)

1.16 (3H, S), 263 (3H, S), 5.17 (1H), 5.50 (1H).

As _{C 23 H 46 N 6 O 9} · H 2 O: Elemental Analysis

Calc .: C 48.58; H 8.51; N 14.78%

Found: C 48.97; H 8.15; N 14.52%

Fraction No. 109-137 was concentrated to dryness under reduced pressure to afford 6′-N, 3 ″ -N-demethyl-1- [L-(-)-α-hydroxy-γ-aminobutyl] XK-62-2 (hereinafter Compound IV) 98 mg is obtained.

Infrared absorption spectrum ν _c = 0,1,640 cm ^-1

NMR Spectrum in ppm in TMS

1.26 (3H, S), 5.23 (1H), 5.97 (1H).

As _{C 22 H 44 N 6 O 9} · H 2 O: Elemental Analysis

Calc .: C 47.64; H 8.36; N 15.15%

Found: C 48.01; H 8.72; N 15.42%

Example 2

169.4 mg (0.3 mM) of Ca 2 and 24.0 mg (0.6 mM) of caustic soda are dissolved in 15 ml of 50% aqueous dimethylformamide solution, and 98.8 mg (0.6 mM) of red blood salt is added at once and the reaction is performed at 30 ° C. overnight. The reaction solution was passed through a column with 20 ml of Amberlite IRC -50 (H ⁺ type), washed with 100 ml of water, passed through 2.0N ammonia water, and about 25 ml of a fraction developed with ninhydrin were concentrated under reduced pressure and almost yellow. 163 mg of residue are obtained. In the same manner as in Example (1), silica gel column chromatography was performed to recover 53 mg of Compound II as an unreacted raw material, followed by 18 mg of Compound III, 42 mg of Compound I, and 9 mg of Compound IV, respectively.

Example 3

282.4 mg (0.5 mM) of compound II are dissolved in 20 ml of water, and 350 mg of fresh platinum black, first activated with hydrogen, is added. While keeping the temperature at 50 ° C, air is introduced into the reaction liquid as fine bubbles and reacted for 30 hours. 275 mg of the residue obtained by filtration of platinum black after concentration and concentration under reduced pressure was subjected to column chromatography of silica gel in the same manner as in Example 1 to recover 173 mg of unreacted raw material compound II, and then 23 mg of compound III, 73 mg of compound I, and compound Obtain 11 mg of IV each.

Example 4

112.9 mg (0.2 mM) of Compound II was dissolved in 10 ml of water, followed by 189.6 mg (1.2 mM) of potassium permanganate, followed by overnight reaction at room temperature. The reaction solution was passed through a column with 15 ml of Amberlite IRC -50 (H ⁺ type), followed by washing with 100 ml of water, and then driving about 30 ml of a ninhydrin fraction through 2.0 N ammonia water under reduced pressure. Concentrate to get 108 mg of pale yellow residue. In the same manner as in Example 1, silica gel column chromatography was performed to recover 29 mg of unreacted raw material compound II, and then 8 mg of compound III, 27 mg of compound I, and 13 mg of compound IV were obtained, respectively.

Example 5

A solution obtained by dissolving 568.7 mg (1.0 mM) of compound I in 4.0 ml of water and dissolving 98 mg (1.0 mM) of sulfuric acid in 1.0 ml of water under cooling is added. After 30 minutes, cold ethanol is added until precipitation occurs, and the precipitated white solid is filtered to obtain monosulfate of compound I.

Claims (1)

A method for producing an antibiotic derivative of structural formula (B), wherein the antibiotic derivative represented by structural formula (A) is reacted with an oxidizing agent.

N is a positive integer of 1-4.