Fragrant macrocyclic lactones

The present invention relates to the perfume industry and to the field of organic synthesis. It concerns more particularly a perfuming composition or a perfumed products comprising as a perfuming ingredient at least one macrolide of formula ##STR2## having a double bond in one of the positions indicated by the dotted lines and wherein symbol R represents a hydrogen atom or a ethyl group, together with a current perfuming co-ingredient, solvent or adjuvant.

The invention further concerns a method to impart improve, enhance or modify the fragrance of a perfuming composition or of a perfumed product, which method comprises thereto at least one macrolide of formula (I) as defined above.

Other objects of the invention are novel compositions of matter, for example, consisting of a mixture of said macrolides, the mixture having a content of at least 70% by weight of macrolides of formula (I) wherein the double bond has an (E) configuration. Or yet, of 11-tetradecen-14-olide having a chemical purity of 90% or more.

The invention also relates to an original process for the preparation of macrolides (I).

The compounds of formula (I) above are macrocyclic lactones, the structures of which have been mentioned in the prior art, typically in the context of synthetic studies aimed at the preparation of large carbocycles or in reasons where these lactones are intermediate products which are chemically converted into structure related end products, with out being properly characterized.

U.S. Pat. No. 3,890,353, for example, describes a process for the preparation of saturated macrocyclic lactones having 14 to 17 carbon atoms in the ring, via complete hydrogenation of intermediate mixtures of saturated and unsaturated lactones. In the context of this disclosure, there is described an intermediate mixture of 14-methyl-14-tetradec-(11 and 12)-enolide and 14-methyl-14-tetradecanolide, the hydrogenation of which leads to the latter. This mixture is disclosed purely as a chemical intermediate in said process, and there is no teaching of the chemical or physical characteristics of 14-methyl-14-tetradec-(11 and 12)-enolide, its isomeric composition for instance remaining totally unknown.

A. G. Cameron et al., on the other hand, fully characterize (E)- and (Z)-12-tetradecen-14-olide, used as intermediates in the context of Ireland enolate Claisen rearrangement type reactions (see J. Chem. Soc. Perkin Trans. I, 1986, 161).

This article is however silent as regards any other potential use or property of the described tetradecenolides.

It is also known in the art that some higher homologues of compounds (a) are prized perfume ingredients. In this context, one can cite for example 15-pentadecanolide, a saturated higher homologue, better known under the tradename of Exaltolide® (trademark of Firmenich SA. Geneva. Switzerland), which is described in the U.S. Patent cited above.

A more recent document EP-BI-424 787, describes useful perfuming ingredients formed of (11,12)-pentadecen-15-olides.

It is, therefore, with great surprise, that we have discovered that, in spite of the structural teachings cited above, there is no suggestion in the prior art of the object of the present invention, i.e. the advantageous application of the newly discovered and unexpected fragrance properties of lactones (I) and their mixtures.

We have now established that lactones (I) are not only extremely useful fragrance ingredients, but that they possess in fact odors which are quite specific and original, distinct from those of their known homologues. These compounds reveal themselves capable of creating new olfactive effects, unsuspected heretofore, as becomes apparent from the following description.

As previously cited, a main object of the invention is therefore a perfuming composition or a perfumed product, comprising as a perfuming ingredient at least one macrolide of formula ##STR3## having a double bond in one of the positions indicated by the dotted lines and wherein symbol R represents a hydrogen atom or a methyl group, together with a current perfuming co-ingredient solvent or adjuvant.

As a result of the presence of the double bond in their structure, lactones (I) can occur in four isomeric forms (11-cis,11-trans, 12-cis and 12-trans), corresponding to the cis- or trans-configuration of said double bond, and these four isomers can possess distinct odors.

According to a preferred embodiment of the invention, the perfuming compositions or the perfumed products will comprise a mixture of macrolides, which mixture has a content of at least 70% by weight of macrolides (I) wherein the double bond in position 11 or 12 of the ring has an (E) configuration.

We have in fact observed that as a result of the original process for their preparation that we describe further on, such mixtures can be directly obtained from the synthesis and have proved to be superior odor ingredients.

These compounds can in fact be used in a great variety of perfumery applications. It has been established that they can impart to the compositions and consumer products to which they are added musky fragrances which are accompanied by other odor nuances rendering lactones (I) extremely useful for replacing some known materials, the use of which was prevalent in the past for imparting musky fragrances but is fast becoming very restricted for toxicological and/or environmental reasons.

Compounds (I) fulfill just the necessary conditions to perform such a role and this is especially true as regards II -tetradecen-14-olide and the mixtures of this lactone with 12-tetradecen-14-olide, which are all preferred perfuming ingredients of the invention. They develop a very pleasant and fine musky odor, characterized by a strong note of the so called "nitromusk" type, sweet animal and strongly reminiscent of the odor of ox blood. The perfumery value of these ingredients is judged by the perfumer experts to be immense, as their fragrance effect makes it possible to return to the classical musk perfumery effects of the sweet animal, powdery, ox blood type, which have been for many years the basis of perfumery creations and can no longer be easily reproduced since the restrictions on the use of compounds such as Musk Ketone and Musk Ambrette.

According to the invention, the use of mixtures of 11-tetradecen-14-olide and 12-tetradecen-14-olide wherein the content in (E)-11-tetradecen-14-olide is 80% by weight or more of the weight of the mixture is particularly advantageous for the preparation of perfuming compositions and perfumed products of varied nature.

These preferred perfuming ingredients of formula (1) wherein R represents hydrogen, although they are somewhat less powerful and tenacious than some of their known higher homologues, turned out to be preferred to the latter for certain perfume applications to which they bring this classical musk effect much sought after by the perfumers. When tested in current commercial perfumes in which they were made to replace the key ingredients Musk ambrette or Musk ketone, the compounds of the invention were also repeatedly preferred and this even when compared to known and well-liked substances such as Exaltolide® (origin: Firmenich SA. Geneva. Switzerland). 5-methyl-5-pentadecen-1-one (see U.S. Pat No. 5,354,735 for example; origin: Firmenich SA. Geneva. Switzerland) or yet (11,12)-pentadecen-15-olide (see U.S. Pat. No. 5,266,559 for example; origin: Firmenich SA. Geneva Switzerland).

As for the ingredients of formula (I) where R represents a methyl group, they impart to the compositions and consumer products into which they are incorporated a really nail musk quality, reminiscent of the odor of the tincture of the musk gland from the musk deer. Once again, the mixtures of 11-pentadecen-14-olide and 12-pentadecen-14-olide which contain at least 70% or more by weight of macrolides having a double bond of (E) configuration are particularly appreciated.

The macrocyclic lactones of formula (I) will be typically used in the perfuming compositions and perfumed products of the invention in admixture with the usual perfuming co-ingredients, solvents and adjuvants, as is current in the art and as a function of the type of fragrance that one desires to achieve and the creative imagination of the perfumer. Such current perfuming co-ingredients belong to all the usual chemical classes such as alcohol, ethers, esters, ketones, aldehydes and the like. It is clear that it is not warranted here to list such ingredients in a detailed manner, as their nature is part of the general knowledge of the skilled person as represented for example by, but certainly not restricted to, the teaching of textbooks such as the work of S. Arctander, Perfume and Flavor Chemicals, Montclair, N.J., USA (1969) and others. One can cite in this context and as is apparent from the examples, the fact that, for example, 11-tetradecen-14-olide and its mixtures above-mentioned can marry particular well with other known macrocyclic lactones such as Exaltolide® (origin: Firmenich SA. Geneva, Switzerland) and Astrotone to provide improved fragrances with the prized "nitromusk" character.

The concentrations in which these lactones (I) can be added to the perfuming compositions and perfumed products of the invention vary in a wide range of concentrations, the values of which are dictated by the nature of the end product and by the nature of the other ingredients present in the composition. Typical concentrations in perfumes and perfuming concentrates are of the order of 1 to 10 or 20% by weight, relative to the weight of the composition but can be higher, depending on the degree of odor contribution from these compounds that is desired for the overall effect in a particular fragrance creation. Quite generally too, much lower concentrations will be required for perfuming consumer products other than perfumes, colognes and the like. One can cite as typical perfumed end products of this kind, soaps, bath and shower gels, shampoos, hair-conditioners and other hair-care products, cosmetic preparations such as skin products and other, body or air-deodorants, fabric detergents and softeners, dishwashing products or yet other household and cleaning products.

The invention also includes novel compositions of matter consisting of a mixture of macrolides of formula ##STR4## having a double bond in one of the positions indicated by the dotted lines and wherein symbol R represents a hydrogen atom or a methyl group, said mixture having a content of at least 70% by weight of macrolides of formula (a) wherein the double bond has an (E) configuration.

Preferred compositions of matter of the invention amongst those above, include the mixtures of 11-tetradecen-14-olide and 12-tetradecen-14-olide and, more particularly, those among the latter which contain around 80% by weight of (E)-11-tetradecen-14-olide or more.

As pointed out before, these compositions of matter possess entirely surprising odor properties, whereas there is no suggestion in the prior art references cited which could have given guidance to the particular combinations of macrolides above-mentioned.

These novel compositions of matter can be prepared by a process which comprises the fragmentation of a hydroperoxide of formula ##STR5## wherein R has the meaning indicated in formula (I), in an inert medium and in the presence of transition metal salts.

Useful macrolide preparation methods of this type have been described in the prior art ay by S. L. Schreiber and his collaborators, in J. Amer. Chem. Soc. 1980, 102, 6163 and Tetrahedron, 1986, 42, 2945, which consist of a homolytic cleavage of the peroxide bond, promoted by an excess of iron sulphate, followed by the fragmentation of the resulting alkoxy radical by means of a methanol solution saturated with cupric acetate. A similar process is described in EP 424 787.

In a more recent publication, RU-C-1436465, it has been suggested to use a catalytic amount of copper acetate, in a solvent consisting of a ketone, to improve the yield in 15-pentadecanolide and in the intermediate unsaturated analogues. Although the authors seem to suggest that the use of ketones as solvents provides better results, the method seems to be in fact quite general and many other types of current solvents which are inert under the reaction conditions can be used, such as esters, namely acetates, formates and proplonates, ketones, some of which are cited in the Russian document above-mentioned, alcohols, or yet aliphatic hydrocarbons, both cyclic and acyclic, as well as aromatic hydrocarbons.

Likewise, many other inorganic or organic copper salts or complexes can be used as the catalyst, amongst which there can be cited the copper halides, chlorides in particular, complexes such as copper acetylacetonate, copper carboxylates such as the acetate, propionate or butyrate, or yet copper caproate, benzoate, pivalate, valerate or isovalerate, laurate and 2-etylhexanoate, all of which are current reagents in copper catalysis. Other examples include copper octanoates, decanoates and naphthenates, of current use in the paint industry.

The reaction can be carried out at a variety of temperatures, the reflux temperature of the solvent, as suggested in the Russian document, being however quite convenient as it allows for azeotropic elimination of the water formed.

As for the starting products, one of the hydroperoxides (II), i.e. 14-methyl-13-oxabicyclo[10.3.0]pentadecan-12-yl hydroperoxide, is a known compound, described for example by J. Becker et al in Helv. Chim. Acta 1971, 54, 2889. The other star product 13-oxabicyclo[10.3.0] pentadecan-12-yl hydroperoxide, which has never been described in the prior art, can be prepared from 13-oxabicyclo[10.3.0]pentadec-1(12)-ene (see, for example, U.S. Pat. No. 3,856,815), by reacting the latter with hydrogen peroxide, in an inert organic solvent and in the presence of an acid catalyst, in accordance with prior described methods (see, for example, J. Becker et al., refs. cited or yet U.S. Pat. No. 5,266,559). If desired, the preparation of the compounds (II) can of course be carried out in the solvent medium used for their subsequent fragmentation.

This process allows the preparation of macrolides (I) in excellent yields and under reaction conditions which are quite convenient for profitable industrial application. Furthermore, it is in fact a general method for preparing unsaturated macrocyclic lactones, amongst which known higher homologues thereof.

The invention will now be described in further detail by way of the following examples, wherein the temperatures are indicated in degrees Celsius and the abbreviations have the usual meaning in the art.