PT85433B - PROCESS FOR THE OBTAINMENT OF ABIETIC ACID DERIVATIVES AND ANTIMICROBIAL COMPOSITIONS OF THESE DERIVATIVES - Google Patents

Abstract

The cpds. of formula (I) with high anti-microbial activity relative to known cpds, for use in wide-spectrum fungicides, are obtained by a new process from colophonium, abietic acid, dehydro-abietic acid, or salts or esters of these.

Description

DESCRIPTIVE MEMORY

This invention relates to abietic acid derivatives with biological activity.

The resinic acids that make up rosin include abietic acid and other acids that are easily isomerized to abietic acid, and therefore rosin is a convenient raw material from which many derivatives have been prepared and investigated. Abietic acid is easily dehydrogenated to dehydroabietic acid (I) having the structure

The fungicidal properties of 7-oxo-hydrohydetic acid (II)

were described by Franich et al. in Physfological Plant Pathology

(1983) 23, 183-195. Molluscicidal activity for 13-hydroxy-desisopropyl-de-hydroabietic acid is also described by Rogers et al. in

Identif. Anal. Org. Pollut. Waterk 1981) 2, 1097-1113 [Chem. Abstr., 102.126769a],

During the studies carried out, it was concluded that the compounds that have improved antifungal properties are those of the general formula (III)

COOR where R represents H, a cation, ex. an alkali metal, calcium ion, zinc ion or copper ion, or an alkyl group containing up to six carbon atoms. These compounds exist in cis and trans forms with respect to the methyl group and hydrogen in positions 10 and 5, respectively.

The compounds of formula (III) in which R represents methyl have already been prepared by oxidation with chromic acid of methyl desisopropyl dehydroabietate, by Ohta et al. in Chem Pharm. Bull (1954) 5 (2), 91-96, and by Grove et al. in J Chem. 5oc. (1961) 1105-1112, but this reaction occurs with low yields of the desired products, especially in the case of compound c / s. Furthermore, those authors do not mention any biological activity or other valuable property

of these compounds.

It has also been concluded that a much superior synthetic method for producing the compounds of formula (III) is by photo-oxygenation of the cis form or the trans form of the deisopropyl 1-dehydroabietic acid (IV) or the appropriate salts or esters derived therefrom , according to the following scheme:

(IV, cis) h ό ------->

(IV, trans)

(III, trans)

In relation to the chemical oxidation method already known, the photo-oxygenation of the starting materials according to the present invention gives rise to the desired products without significant contamination by secondary products and in yields that can be as high as 90% or more,

The transposed cis-form compounds of formula (III) are both active. It is therefore possible to use as a starting material a mixture of the trans-cise forms of desisopropyl-hydroxyabetic acid, or salts or esters derived therefrom, produced by known methods of deisopropylation. dehydroabietic acid or salts or esters derived therefrom, e.g. by treatment with aluminum chloride. The cis and trans compounds of formula (III) can be easily separated, if desired, to produce pure compounds.

The compounds of formula (III) can be used as antimicrobial agents or formulated as antimicrobial compositions for the treatment of various microorganisms including fungi and other organisms. Particularly high levels of antifungal activity were found against Cíadosporium cucumerinum, Rhyzopus oryzae, Fusarium oxysporum, Fusarium moniiiformis, Sporotrichum pulvurulentum and Myrothecia verrucaria.

The process of the present invention can be carried out by photo-oxygenating the appropriate compound in solution in organic solvents. Concentrations of 0.1-0.3M in acetone, or other suitable solvents, can be used. The solution is conveniently irradiated for 10 hours or more to produce the desired yield of the product after removal of the solvent.

This invention is described in more detail in the following Example 1.

For convenience, the overall process starting from rosin is described, since it is a suitable starting material for use on a commercial scale.

EXAMPLE I

Rosin (20 g) is methylated with excess diazomethane in diethyl ether: methanol (9: 1) to give a mixture of resin-methylated acids (21 g) containing at least 60% methyl abietate. After purification to remove oxidized products, a light colored gum (18.4 g) is obtained.

g) which is dehydrogenated with 5% palladium on charcoal (2% by weight) at 210-220 ° C for 2.5 hours, then dissolved in dichloromethane and filtered to remove the catalyst, to give a clear gum (17.5 g ) containing 60% methyl dehydroabietate. This mixture (17.5 g) is dissolved in benzene (1000 ml) and anhydrous aluminum chloride (30 g) is added, leaving at room temperature for 16 hours, adding water and extracting with diethyl ether. The ethereal solution is washed with 5% sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a mixture (16 g) of the c / s forms (54% ) and trans (28%) methyl deisopropyl 1-dehydroabietate. The c / s isomer is separated as a pure compound by crystallization from methanol. The trans isomer is separated from the mother liquors by silica column chromatography with silver nitrate.

C / s methyl deisopropyl 1-dehydroabietate (4 g) in acetone (0.2 M) is irradiated in a quartz container with a mercury lamp of

high pressure (125 W) for 17 hours. The solvent is removed under reduced pressure to give a methyl 7-oxo-desisopropyl 1-dehydroabietate gum (3.6 g, 90%), as an oil, [a] _D -77.0, Z _max (EtOH) 253, 296 nm. The same reaction, when carried out on the trans isomer, gives about 90% yield on trans 7-oxo-desisopropyl-1-dehydroabietate methyl, mp 50-2 ° C, [a] _D +4, 1, À _max (EtOH) 252, 298 nm.

EXAMPLE 2

The photooxygenation process described in Example 1 can be varied using alternative solvents and reaction conditions. The following table summarizes typical results obtained.

TABLE

Material of match Vase of reaction Solvent Time (H) Products (% *) III, cis II 1, trans IV, c / s Pyrex t-BuOH 86 90 - (0.2M) Quartz t-BuOH 48 92 - Quartz Me ₂ C0 17 > 95 IV, trans Quartz t-BuOH 44 - 90 (0.2M) Quartz Me ₂ CO 17 - > 95

* Values determined by relative integration of the corresponding chromatographic peaks

Claims (9)

A process for the preparation of a compound of formula in which R represents H, a cation or an alkyl group containing up to 6 carbon atoms, which involves subjecting c / s or trans desisopropyl 1-hydroxy acid, or a salt or a ester derived from it, photo-oxygenation. A process according to claim I wherein the reaction is carried out in an organic solvent. A process according to claim 2, wherein the solvent is acetone. A process according to any of claims 1 to 3, in which esterified rosin is dehydrogenated to produce a dehydroabietate ester, the resulting product being deisopropylated to produce a 1-dehydroabietate ester, and the resulting product is subject photooxygenation to produce a compound of the formula defined in claim 1. A process according to claim 4 in which methylated rosin is used. A process according to claim 4 or 5 wherein the separation of the c / s and trans compounds is carried out before or after the photooxygenation step. A process according to claim I, comprising a compound of formula as defined in claim 1, which constitutes an antimicrobial agent. A process according to claim 7, wherein R represents methyl. A process for obtaining an antimicrobial agent according to claim 7, wherein R represents H or a Na, Ca, Zn or Cu ion. A process of preparation for obtaining an antifungal composition comprising a compound as defined in claim 7, 8 or 9.