JPS63185980A - Production of demalonyl compound of macrolide lactone - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Macrolide lactones with malonic acid half esters, such as nihuimycin, guanidylphungin A1 copiamycin or azaromycin F4, exhibit a clearly better antifungal action after removal of the half ester. These demaronyl compounds are fungicides, but their starting compounds only have fungistatic activity (K,
Written by Takesako rJ, Antibiot
, J 2g, 1363 (1985); K, T
Author: akesako r J, Antibiot, J
29°713 (1986)]. Furthermore, the solubility of the demaronyl compound in water is also better.

Previously, direct hydrolysis of macrolide malonic acid half esters to the corresponding demaronyl compounds was not considered possible. Due to the hydroxyl group in the β-position relative to the hemisecure group in the six-membered ring of niphimycin,
In direct hydrolysis, for example, reverse aldol splitting occurs. This produces a mixture of several components, the fractionation of which has hitherto been unsuccessful (J, 1. Westley, rJ, Chew, Soc, Cheap, Co.
mmun, J71 (1970): Ta, kesak
Author: r J, Antibiot, J 2g,
1363° (1985); f, Weller
-rllelv by 3chierlein.

See Chew, ^ctaJ 66, 226 (1983)].

It is generally accepted that after alkylation of the hemiacetal group in the macrolide lactone, the malonic acid group can be removed. However, it is known that the biological action of this type of alkyl macrolide is not very good (K; Takesak
Written by Mr. o rJ.

Antibiot, J 28. 1363 (1985
) and 29. 713 (1986)].

Surprisingly, it has been found that according to the present invention, the malonic acid group can be directly hydrolyzed and removed in the presence of a base under appropriate conditions without reverse aldol splitting.

Accordingly, the present invention provides the following general formula I in the presence of a base:
It is assumed that the tA group represents a malonyl group.

The present invention relates to a process for producing demaronyl compounds of macrolide lactones, which comprises hydrolyzing a compound of formula I (excluding compounds of formula I in which R1 and all R'' are simultaneously hydrogen).

Particularly preferred embodiments of the present invention are detailed below. The invention is also as defined in the claims.

A compound of general formula 1 is dissolved in a suitable solvent. Examples of solvents that can be used are polar solvents such as water, alcohols or mixtures thereof.

Preferred solvents are lower alcohols such as methanol, ethanol, n-propanol, iso-propanol and n-, iso- or tert-butanol.

Add a suitable base to the solution. Amines and metal hydroxides, such as hydroxides of alkaline earth metals or alkali metals, are suitable, and among these, the above-mentioned alkali metal hydroxides, sodium hydroxide or potassium hydroxide, are particularly preferred. Good results have also been obtained when using alcoholades as bases, especially alkaline earth metal and alkali metal alcoholades of lower alcohols, particularly preferably sodium and potassium alcoholades. If the compound to be hydrolyzed is previously dissolved in the alcohol, it is expedient to use an alcoholade of the alcohol for the hydrolysis.

The reaction can be carried out at -30°C to +60°C.

However, the preferred temperature range used is between 0° and 40°
℃, and room temperature is particularly preferred. The time for incubating the mixture of compound to be hydrolyzed and base will vary depending on the reaction temperature. Cultivation times of about 5 to 60 hours, especially 24 hours, have proven advantageous.

It is possible to adjust the number of malonyl groups to be removed by adjusting the reaction time. That is, for example, under the above conditions, niphimycin (one malonyl group) can be produced from amycin (two amalonyl groups) over a reaction time of about 1 to 3 hours.

The intended subsequent use will determine whether the hydrolyzed compound is isolated or not. For isolation, the pH of the reaction mixture is adjusted to a value of 6 to 8. After removing the solvent by distillation, the compound is purified by fractionation on a suitable adsorbent such as silica gel, alumina, etc. and elution with a polar organic solvent or a mixture thereof.

The present invention will be explained in detail below using examples.

Unless otherwise stated, percentages are by weight.

Examples: 1. Preparation of demaronyl compound a. Amycin 1 g (0
,'81 mmol) in sodium hydride (50% in oil)
Suspension) Stir with 100xy at 20°C for 24 hours. Neutralize with 5N hydrochloric acid and then remove the alcohol by vacuum distillation. The resulting syrup was mixed with ethyl acetate/methanol/water (15:2:1,800x (! and 8:2:1
;v:v:V) on silica gel 1009. Crystallization from ethyl acetate/methanol gives 770 my (90%) of the demaronyl compound in which R1 and all R' represent hydrogen.

b. Nihuimycin 1 in methanol 50 pass
g (0,87 mmol) of sodium hydride (5
Stir with 60 gg of 0% suspension at 20° C. for 24 hours. Neutralize with 5N hydrochloric acid and work up as described in Example 1, a. above.

8081 g (88%) of the demaronyl compound in which R1 and all R2 represent hydrogen are obtained.

Example 1 above, except that the C1 reaction was stopped after 2 hours, a.
Niphimycin 920 was prepared by the procedure as described in
11 g (93%) are obtained.

2. Use of demaronil compound as an antifungal agent The antifungal effect was tested in vitro on yeast (Candida albicans) and mold (Aspergillus niger).
[Materials and Methods: r Mykosen J 27.14 (1
Microtitration method published in 984)
tra-tion technique)]. As can be seen from Table A below, in these in vitro tests, the demaronyl compound prepared according to the invention, in which R1 and all R'' are hydrogen, exhibited good antifungal properties, superior to that of the reference material niphimycin. show.

Table A Niphimycin 7,83.9 Demaronyl Compound 3.9 ' 1.9
5 Patent applicants: 2 people other than Hoechst Akchengesellschaft

Claims (1)

[Claims] 1) In the presence of a base, the following formula I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ I (In the formula, R^1 and R^2 are independently hydrogen or malonyl group, In that case, not more than 1 R^3
The substituent represents a malonyl group. A method for producing a demaronyl compound of a macrolide lactone, which comprises hydrolyzing a compound represented by formula I (excluding compounds of formula I in which R^1 and all R^2 are hydrogen at the same time). 2) The method according to claim 1, wherein amines, alkali metal or alkaline earth metal hydroxides and (or alkali metal or alkaline earth metal alcoholates) are used as the base. 3) Hydroxide as the base 3. A process according to claim 2, wherein sodium or potassium hydroxide and/or a lower alcoholate is used. 4) The method according to one or more of claims 1 to 3, wherein the reaction is carried out in a lower alcohol as a solvent. 5) The method according to one or more of claims 1 to 4, wherein the reaction is carried out at -30°C to +60°C. 6) The method according to claim 5, wherein the reaction is carried out at 0 to 40°C. 7) The method according to claim 6, wherein the reaction is carried out at room temperature. 8) A method according to one or more of claims 1 to 7, wherein the reaction mixture is incubated for 5 to 60 hours.