Process for preparing macrocyclic ketol actones.

0001Macrocyclic ketolactones of the formula<chemistry id="chem0001" num="0001"><img file="EP0098367A2_D0001.tif" /></chemistry>where n = 6 to 12 and m = 0 to 3 and R₁ and R₂ independently of one another are hydrogen or an alkyl radical with 1 to 4 carbon atoms, in particular a methyl radical, are generally known as intense and pleasantly fragrant musk fragrances, cf. Ohloff, advances in chemical research 12, 203 (1969).

0002According to DE-OS 24 10 859 representatives of I with n = 9 to 13 and m = 0 to 2 and R₁, R₂⁼ H, -C^H₃, -CH₂CH₃ by reacting the bicyclic enol ethers<chemistry id="chem0002" num="0002"><img file="EP0098367A2_D0002.tif" /></chemistry>made with ozone. According to IJ Borowitz et al. (J. org. Chem. 31, 3032 (1966) and 37, 581 (1972), the ketolactones I with n = 4 to 6 and m = 1.2 and R are obtained₁, R₂ = H from the compounds II also by reaction with derivatives of perbenzoic acid.

0003These two methods are unsatisfactory in several ways.

0004<ul id="ul0001" list-style="none"><li>1. Ozone is with a MAK value of 0.2 mg / m³ an extremely toxic gas. An apparatus on an industrial scale is therefore complex, the implementation of such a process is not without problems.</li><li>2nd The complex ozonolysis poses work-up problems (cf. Borowitz et al., J. Org. Chem. 31, 3032 (1966).</li><li>3rd If perbenzoic acid or its derivatives are used for the oxidation, these aromatic peracids must first be prepared from hydrogen peroxide and benzoic acid. The yields for this are 80%.</li><li>4th The removal of the water-insoluble benzoic and / or perbenzoic acid requires several purification steps.</li><li>5. The yields of ketolactones are - apart from the unsubstituted 6-oxo-nonanolide (n = 4, m = 1, R₁, R₂= H) - unsatisfactory.</li></ul>

0005The object of this invention was therefore to provide an improved process for the preparation of the ketolactones I with n = 6 to 12, m = 0 to 3 and R.₁ , R₂= H, C₁-C₄- Develop alkyl.

0006It has now been found that the bicyclic enol ethers of the formula II can be oxidatively opened to the ketolactones I in good yield by means of aqueous hydrogen peroxide / formic acid solutions. As can be seen from the experimental part, the process can be carried out without problems. In particular, no time-consuming separation operations are required.

0007The reaction path found is surprising for the person skilled in the art. According to Borowitz et al. This is because the reaction of bicyclic enol ethers with moist peracid does not give ketolactones, but glycols of the structure<chemistry id="chem0003" num="0003"><img file="EP0098367A2_D0003.tif" /></chemistry>which then have to be converted to the ketolactones I with lead tetraacetate.

0008Another method of oxidation with organic peracids is described in DE-PS 20 65 550 (see also DE-AS 20 26 056). Then a solution of 13-oxabicyclo- (10.4.0) -hexadecen- (1) in 90% acetic acid is treated with a mixture of 52% hydrogen peroxide and concentrated sulfuric acid.

0009The hydroperoxide adduct obtained is introduced into boiling xylene and gives a mixture of pentadecanolide, pentadecen-11-olide and 12-hydroxypentadecanolide, but not a cyclic ketolactone analogous to formula I.

0010It is crucial for the process according to the present invention that a mixture of formic acid and aqueous hydrogen peroxide is used.

0011The process is primarily used for bicyclic enol ethers, where n = 6 to 12, m = O to 3 and R₁ and R₂ independently of one another hydrogen or an alkyl radical having 1 to 4 carbon atoms, preferably n = 6 to 10 and R.₁ and R₂ independently of one another are hydrogen or a methyl radical. The process is not limited to bicyclic enol ethers: it is basically suitable for the oxidation of electron-rich olefins.

0012The oxidative opening of the bicyclic enol ethers II expediently takes place by dissolving them in a solvent and adding a mixture of aqueous hydrogen peroxide and formic acid and reacting them at a temperature between -20 ° C. and +120 ° C.

0013Particularly suitable solvents are 1,2-dichloroethane, dichloromethane, trichloromethane, chlorobenzene and acetic acid and formic acid, and also mixtures of these substances. The reaction temperatures are generally between 20 and 80 ° C, preferably between 40 and 70 ° C. When the reaction has ended (1 to 4 hours), the aqueous phase is separated off, the organic phase is washed free of acid and then the dried residue is fractionated.

0014The serving as educts bicyclic enol ethers, such as. B. 12-Oxa-bicyclla (9,3, O) tetradecen- (1), 13-Oxa-bicyclo- (10,4,0) hexadecen- (1) and the 14-Oxa-bicyclo (11,4, 0) -heptadecen- (1) are known and can be prepared by known processes (DE-OS 21 .36 496, DE-OS 20 26 056).

0015Accordingly, the following may be mentioned as ketolactones which can be prepared by the process according to the invention: 11-oxotridecanolide, 12-pentadecanolide, 13-hexadecanolide.

0016The ketolactones obtained can be known in the perfume very valuable unstabilized macrocyclic lactones, such as. B. Exaltolid, convert (DE-OS 27 31 543, J. org. Chem. USSR 15, 1285 (1979).

0017For fragrance compositions, the ketolactones produced by the process according to the invention can be used as musk components and fixatives (DE-OS 24 10 859).

example 1

001844 g (0.2 mol) of 13-oxa-bicyclo (10,4,0) hexadecene (1) were dissolved in 150 ml of chloroform. The mixture was heated to boiling with stirring and nitrogen blanket. Then a mixture of 14 g (0.3 mol) of formic acid and 34.8 g (0.6 mol) of H was added dropwise₂0₂ (as a 60% aqueous solution) without heating so quickly that the reflux was maintained. After the addition had ended, the mixture was left to react for a further 3 hours at boiling temperature, washed twice with water, twice with aqueous sodium hydrogen carbonate solution and again with water, the organic phase was dried and 12-oxo-pentadecanolide was distilled off.<tables id="tabl0001" num="0001"><img file="EP0098367A2_D0004.tif" /></tables>

Example 2

0019.45 g (0.2 mol) of 15-methyl-13-oxa-bicyclo (10,4,0) hexadecene (1) were prepared according to Example 1 with H₂0₂/ Formic acid converted to 12-oxo-14-methyl-pentadecanolide.<tables id="tabl0002" num="0002"><img file="EP0098367A2_D0005.tif" /></tables>

Example 3

002041 g (0.2 mol) of 10-methyl-9-oxa-bicyclo (6.5.0) tridecen (1) were prepared according to Example 1 with H₂O₂/ Formic acid converted to 8-oxo-12-methyl-dodecanolide.<tables id="tabl0003" num="0003"><img file="EP0098367A2_D0006.tif" /></tables>