HU213864B - Process for the preparation of hypoallergenic moss oils - Google Patents

Abstract

 In the process of the present invention, the primer seed or its central nutrient or, preferably, the alcoholic acid in an aliphatic or aromatic melting agent is reacted with a metal hydride 20 to 80 CC, and the reaction product is solubilized and purified in a manner known per se. ŕ

Description

(57) EXTRAS

In the process according to the invention, the starting moss oil or its concentrate or, preferably, its absolutate in an aliphatic or aromatic solvent is reacted with a metal hydride at 20-80 ° C, and the reaction product is isolated and purified in a manner known per se.

Description: 7 pages (including 2 pages)

HU 213 864 B

HU 213 864 Β

The present invention relates to the production of moss oils characterized by hypoallergenicity. "Hypoallergenic" means that the oils have significantly lower allergenic activity and exhibit excellent odor intensity in perfume compositions.

Because of their typical woody nature, moss oils are highly sought after by perfumers and fragrances such as perfumes. the so-called "Chypre" and "Fougere" perfumes play an important role. Moss oils are produced by solvent extraction of lichens, e.g. especially oak moss oil, Evemia prunastri L. and wood moss oil, especially Evemia furfuraceaL. can be used as starting material. Worldwide, approximately 6,000 tons of lichen are treated for perfumery purposes [P. Vigne, Parfums, Cosmetiques, Aromes (78), 97-105. (1987)] and estimated annual sales close to $ 35 million.

Moss extracts - e.g. the most commonly used moss absolutate or concentrate as a moss oil product - is known to cause sensitization reactions on human skin. According to several research groups, some mosaic oil components, in particular ethyl hematomate (I), ethyl chloro hematomate (II), atranorin (III) and chloro-atranorin (IV), are involved in allergenic reactions. triggering.

No. 202,647. According to the method described in European Patent Publication (Shiseido Company Ltd), hypoallergenic moss oils are prepared by chromatography, solvent extraction, countercurrent partitioning and membrane separation of moss oil, followed by catalytic hydrogenation and / or alkaline treatment. The allergenic materials thus removed are structurally aldehydes and include the aforementioned ethyl hematomate (I), ethyl chloro hematomate (II), atranorin (III) and chlorratranorin (IV).

No. 468,189, published later. According to the procedure described in European Patent Publication No. Roure S.A., hypoallergenic moss oils are prepared by: the moss absolutate or concentrate is reacted with an amino acid or amino acids in an alcoholic solution under single-phase conditions and the insoluble allergenic compounds of formulas I to VI are removed.

The formulas (I) to (VI) of the allergenic materials are shown on the formula page.

According to the above procedures, the concentration of allergenic compounds of formulas I to VI is below the critical values (0.05-1%) as determined experimentally by allergen tests.

It is an object of the present invention to more extensively remove the aforementioned aldehydes of formulas I to VI by an economical process without significantly affecting the original color and odor intensity of the starting moss oil. It is therefore an object of the present invention to provide moss absolutates or concentrates having a highly reduced allergenic activity.

According to the present invention, the above object is achieved by the use of a moss extract, e.g. concentrate or absolute, with a suitable reducing agent, e.g. with an alkali metal borohydride which specifically and exclusively reduces the allergenic aldehydes of formulas I to VI to the corresponding primary alcohols.

A further advantage of the new process according to the invention is that it avoids the simultaneous formation of colorants which are unpleasant for certain perfume applications.

Thus, in the process of the present invention, the reaction is carried out in an organic solvent medium between moss extracts (e.g. oils, concentrates or absolutes) and reducing agents (e.g. complex metal hydrides, preferably alkali metal borohydrides, especially lithium or sodium borohydride). juice.

The moss extracts used as starting material are preferably prepared by solvent extraction of lichens. In particular, oak moss concentrates (Evemia prunastri L.) and wood moss concentrates (Evernia furfuracea L.), and preferably their absolutes, can be used.

From the literature [e.g. Reagents for Organic Synthesis, L.F. FieserésM. Fieser, 599-603. and 1049-1055. John Wiley and Sons (1967)] are known for their ability to reduce complex alkali metal hydrides (e.g., borohydrides or aluminum hydrides), aldehydes, ketones and even esters. The aldehyde-type allergenic materials of formulas I to VI contribute only insignificantly to the overall fragrance of moss extracts, but many esters, other aldehydes and ketones are known to be important constituents or major fragrance components of such extracts [R. Tér Heide et al., Qualitative Analysis of the Odoriferous Fraction of Oakmoss (Evemaria prunastri (L.) Ach.), J. Agric. Food. Chem. 23 (5): 950-957 (1975)].

Surprisingly, it has now been found that with the novel process of the present invention, the allergenic compounds of formulas I to VI can be selectively reduced without organoleptically damaging the moss oils. In other words, gas chromatographic assays show that the process of the present invention does not remove any of the aforementioned organoleptically active components, i.e. the organoleptically active ester, in the original moss extract. In addition, the concentration of the allergenic compounds of formula (I) (VI) is much lower than the desired limits after completion of the process (see Table 1). and E. Ehret, P. Maupetit, M. Petrzilka, G. Klecak, Int. J. of Cosm. Science 14: 121-130 (1992)]. A further advantage of the process according to the invention is that the color of the obtained non-allergenic moss oils is very close to that of the original oil and therefore the oils obtained are suitable for most perfume applications.

HU 213 864 Β

Table 1

Aldehyde Desired Concentration Levels (%) in Ethyl Hematomate of Formula (I) <1 Ethyl Chloro-Hematomate of Formula (I) <0.05 (III) + Atranorines of Formula (IV) <0.15 (V) Atranol with Reduced Allergenic Activity &Lt; 0.2 Chlorotranol of formula (VI) < 0.2

In the broadest sense of the present invention, an allergenic moss oil is dissolved in a suitable organic solvent and is preferably treated with an appropriate aldehyde reducing agent used in excess. Suitable reducing agents for the process of the invention are those which are capable of reducing the aldehydes exclusively or at least advantageously relative to the esters. These reducing agents can be classified into different types [see R.C. Larock, Comprehensive Organic Transformations, A Guide to Functional Group Preparations, VCH Publishers, Inc. New York, 527-535 (1989). For the process of the invention, e.g. the following reducing agents may be used:

complex metal or ammonium hydrides (e.g., sodium, lithium, potassium, zinc, tetraethylammonium borohydrides, etc.);

substituted complex metal or ammonium hydrides (e.g., sodium triacetoxyborohydride, potassium triacetoxyborohydride, sodium cyanoborohydride, or tetra (n-butyl) ammonium triacetoxyborohydride) ;

metal hydrides (e.g. diborane or alkali metal or aluminum hydrides, etc.).

Preferably, the reducing agent is lithium borohydride or sodium borohydride.

The reduction may be carried out by known methods. The process is generally carried out in an organic medium, e.g. as reaction medium, e.g. optionally halogenated, aliphatic or aromatic organic hydrocarbons (e.g. hexane, cyclohexane or toluene, etc.), esters (e.g. ethyl acetate, isopropyl acetate, etc.) or alcohols (e.g. methanol, ethanol, etc.) may be used. In addition, ether-type solvents (e.g. tertiary butyl methyl ether, tetrahydrofuran, etc.) or halogenated solvents (e.g. methylene chloride) may be used. Mixtures of the above-mentioned solvents may also serve as reaction media.

The concentration of moss extracts used in the reaction is 5-50% w / w, preferably about 5% w / w. 5-15% w / w.

Reducing agents, e.g. alkali metal borohydrides may be used in an amount of 0.02-0.1 g, preferably 0.03-0.07 g, per g of moss extract. This corresponds to a molar excess of 2 to 5 times, i.e. an excess of 8 to 20 times the reducing equivalent.

The reaction may be carried out using lithium borohydride at 20-80 ° C, preferably 20-30 ° C. When sodium borohydride is used, it is possible to work in an alkanolic (e.g. ethanol) medium, preferably while refluxing the reaction mixture.

The reaction is quenched generally after 30-180 minutes, preferably 30-60 minutes, with sodium borohydride, and usually after 1-2 hours with lithium borohydride.

If water-immiscible solvents (e.g. hydrocarbons, esters, halogenated and aliphatic ethers) are used, the reaction mixture is treated with water or aqueous acid (e.g. 1-10% w / w, preferably 1-3% w / w). Wash thoroughly with aqueous hydrochloric acid) and then wash to neutral with water. The solvent was then removed in vacuo for ca. Distill at a temperature not exceeding 85 ° C. Alternatively, water-soluble solvents (e.g., alcohols or cyclic ethers, e.g. tetrahydrofuran) are used, the solvent is first removed by vacuum distillation, and the residue is redissolved in a water-immiscible solvent (e.g., the solvent mentioned above). way.

The following examples further illustrate the process without limiting the invention to the examples.

Examples

1) Allergenicity

The product strongly reduces its allergen activity in each case by standard well-established skin sensitization and skin reaction methods. The following methods are used:

^x modified Buehler's method in guinea pig and ^x RIPT (repeat injury test) in humans.

Ehret C. et al., International Journal of Cosmetic Scienc. 14: 121-130 (1992)].

2) Analysis The amount of aldehyde of formulas (I), (II), (V) and (VI)

The amount of compound of formula (I), (II), (V) and (VI) present in the product is determined by gas chromatography analysis. We apply an internal standard and work under the following conditions:

^x column: 50 m ^x 0.32 mm internal diameter, bulk silica;

^x stationary phase: CP SiI 5CB (silicone);

^x detector: FID (flame ionization detector);

^x vector gas: helium, 2 ml / min;

^x temperature program: 100-240 ° C, 2 ° C / min; ^x internal standard: methyl 2,4-dihydroxy-3,6-dimethylbenzoic acid

The product contains aldehyde of formulas III and IV

The aldehyde content of the product (III) and (IV) was determined by HPLC. An external standard was used and worked under the following conditions: ^x column: 250 mm long, 4.6 mm internal diameter; ^x stationary phase: RP 18 (reverse phase, particle size: 7 µm);

^x detector: UV at 260 nm;

^x mobile phase A: water acidified with concentrated phosphoric acid to pH 2,8;

B: acetonitrile.

EN 213 864 Β ^x Gradient: Time (min)% A% B Flow (ml / min) 0 80 20 1

5 95 1

5 95 1

The above gradient allows efficient separation of the non-volatile aldehyde of formulas III and IV.

Example 1

Preparation of highly reduced allergenic oak mousse solutisate using lithium skin hydride

Into a 500 ml three-necked flask fitted with a mechanical stirrer, a condenser and a dropping funnel, 15 g of a commercially-rendered oak moss solutizate (Givaudan-Roure, m.p. about 70 ° C) are weighed and 200 ml / volume of nitrogen at room temperature is added. in a volume ratio cyclohexane / isopropyl acetate. To the resulting homogeneous solution, a suspension of lithium borohydride (480 mg, 22 mmol) in cyclohexane / isopropyl acetate (3: 1, v / v) was added dropwise to ca. In 30 minutes. Immediately after the addition, a precipitate formed and a slight increase in the temperature of the reaction mixture (about 0 ° C) was observed. After stirring for a further 2 hours at room temperature, the reaction mixture was carefully quenched with 150 mL of 0.5% w / w aqueous hydrochloric acid and extracted with 3x 300 mL of a 3: 1 v / v cyclohexane / isopropyl acetate mixture. The organic phases are washed once with 150 ml of water, combined and concentrated in vacuo (2.103 Pascal water bath at about 85 ° C.) To obtain 12.78 g (85.2% yield) of oak mousse solutate for GC and HPLC analysis. according to Table I only contains an extremely small amount of the aldehyde of formula (I) (VI).

Table 2

aldehyde initial got Oakmoss Oakmoss absolute absolute (w / w) (w / w) Ethyl of formula (I) -hematommát 2.40 <0.01 Ethyl chloro of formula (II) -hematommát 1.44 <0.01 (III) + (IV) atranorinok 0.58 0.05 Atranol (V) 4.24 0.06 Chlorotropanol (VI) 2.28 <0.01

Example 2

Preparation of oak moss solutizate with highly reduced allergen activity using sodium borohydride

Into a 250 ml three neck flask fitted with a mechanical stirrer, a condenser and a dropping funnel, 14.9 g of a commercially-rendered oak mosaic solutate (Givaudan-Roure, m.p. about 70 ° C) was weighed and then 90 ml / 96 N at room temperature. dissolved in ethanol by weight. Approx. A suspension of 1 g (26.4 mmol) of sodium borohydride in 60 ml of 96% w / w ethanol is added dropwise over 5 minutes. A slight increase in temperature (about 12 ° C) is observed during the addition. The reaction mixture is refluxed for 45 minutes, then the ethanol is distilled off in vacuo (2.102 ³ Pascal) and the residue is taken up in 300 ml of tert-butyl methyl ether. The reaction was carefully quenched with water (150 mL) and extracted with tert-butyl methyl ether (3 x 300 mL). The organic layers were washed once with 150 ml of water, combined and concentrated under vacuum (10.2 Pascal ³⁾ on a water bath not exceeding 65 ° C at approx. 12.78 g (85.2% yield) of oak mousse solutate containing by GC and HPLC analysis an extremely low aldehyde of Formulas I to VI were obtained. The results are shown in Table 3.

Table 3

aldehyde Kiindulási- got Oakmoss Oakmoss absolute absolute (w / w) (w / w) Ethyl of formula (I) -hematommát 3.78 0.11 Ethyl chloro of formula (II) -hematommát 1.46 0.02 (III) + (IV) atranorinok 1.16 0.01 Atranol (V) 3.30 <0.01 Chlorotropanol (VI) 1.92 0.03

Example 3

Preparation of oak mousse solutates with highly reduced allergen activity using sodium borohydride (acid treatment)

To a 250 ml three neck flask fitted with a mechanical stirrer, a condenser and a dropping funnel are weighed 15 g of commercially melted oak moss solutizate (m.p. about 70 ° C) and dissolved in 100 ml of 96% ethanol at room temperature. Approx. A suspension of 1 g (26.4 mmol) of sodium borohydride in 60 ml of 96% w / w ethanol is added dropwise over 5 minutes. A slight increase in temperature (about 15 ° C) is observed during the addition. The mixture was heated under reflux for 45 minutes, then the ethanol was evaporated under vacuum (10.2 Pascal ³⁾ and the residue was taken up in 300 ml of tert-butyl methyl ether. The reaction was quenched by careful addition of 100 mL water and ca. It is acidified to pH 1.5 with 15 ml of 6% aqueous hydrochloric acid. The organic layer is washed once with 150 mL of water and concentrated in a water bath under vacuum (2.103 Pascal) at a temperature not exceeding 65 ° C. 14.42 g (96.1% yield) of oak mousse solutate containing only a very small amount of the aldehyde of formulas I to VI according to GC and HPLC analysis. The results are shown in Table 4.

HU 213 864 Β

Table 4

aldehyde initial got Oakmoss Oakmoss absolute absolute (w / w) (w / w) An ethyl hematomate of formula (I) 3.78 0.05 Ethyl chloro hematomate of formula (II) 1.46 0.02 Atranorines of formula (III) + (IV) 1.16 0.05 Formula (V): atranol 3.30 <0.01 Chlorotropanol (VI) 1.92 <0.01

PATENT CLAIMS

Claims (7)

PATENT CLAIMS A process for the preparation of hypoallergenic moss oils by removing any allergenic material present, comprising reacting the starting moss oil, its concentrate or, preferably, its absolutate, with an aldehyde reducing metal hydride in an aliphatic or aromatic solvent at a temperature of from 20 ° C to 80 ° C. and the reaction product is isolated and purified in a manner known per se. Process according to claim 1, characterized in that the aldehyde reducing agent is an alkali metal hydride, an optionally substituted complex metal or ammonium hydride, preferably an alkali metal borohydride, particularly preferably lithium borohydride or sodium borohydride. employed. Process according to claim 1 or 2, characterized in that the solvent is an optionally halogenated aliphatic or aromatic hydrocarbon, ester, alcohol or ether or a mixture of such solvents. 4. Process according to any one of claims 1 to 3, characterized in that a water immiscible solvent is used, preferably with an alkane carboxylic acid ester of an aliphatic hydrocarbon, more preferably hexane or cyclohexane, preferably ethyl acetate or isopropyl acetate or an aliphatic ether, preferably tertiary butyl methyl ether. mixture. 5. Process according to any one of claims 1 to 3, characterized in that a water miscible solvent is used, preferably alkanol, particularly preferably ethanol or cyclic ether, preferably tetrahydrofuran. Process according to claim 5, characterized in that the reaction mixture is processed (in a water immiscible solvent, preferably in the solvent listed in claim 4). 7. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out at a temperature of 20 to 80 ° C, preferably 20 to 30 ° C, when lithium borohydride is used, and preferably 60 to 80 ° C, when sodium borohydride is used. on. HU 213 864 Β Int Cl ⁶ : C 11 B 9/02 CHO (II) CHO (iii) CHO HU 213 864 Β Int Cl ⁶ : C 11 Β 9/02