(3R) epimer of octahydro-7,7-dimethyl-8-methylene 1H-3a, 6-methanoazulene-3-yl acetate, composition, synthesis process and use of said epimer

Abstract

The first subject matter of the invention is the (3R) epimer of octahydro-7,7-dimethyl-8-methylene-1H-3a,6-methanoazulen-3-yl acetate [(octahydro-7,7-dimethyl-8-methylene-[3R,3aR,6R,8aR]-1H-3a,6-methanoazulen-3-yl acetate) or (R)-norzizaenylacetate] of formula I (I). The subject matter of the invention is also compositions comprising (R)norzizaenyl acetate and also a novel synthesis process and the use of said ester.

Claims

1. An isolated (3R)-epimer of octahydro-7,7-dimethyl-8-methylene-1H-3a,6-methanoazulene-3-yl acetate [(octahydro-7,7-dimethyl-8-methylene-[3R,3aR,6R,8aR]-1H-3a,6-methanoazulene-3-yl acetate) or (2R)-12-norziza-6(13)-en-2-yl acetate] of formula I ##STR00006##

2. A composition containing a (3R)-epimer of octahydro-7,7-dimethyl-8-methylene-1H-3a,6-methanoazulene-3-yl acetate [(octahydro-7,7-dimethyl-8-methylene-[3R,3aR,6R,8aR]-1H-3a,6-methanoazulene-3-yl acetate) or (2R)-12-norziza-6(13)-en-2-yl acetate] of formula I: ##STR00007## wherein (2S)-12-norziza-6(13)-en-2-yl acetate is either absent or present in an amount such that the weight ratio of (2R)-12-norziza-6(13)-en-2-yl acetate to (2S)-12-norziza-6(13)-en-2-yl acetate [(R)/(S)] is greater than 1.2.

3. The composition according to claim 2, wherein (2S)-12-norzisa-6(13)-en-2-yl acetate is absent.

4. The composition according to claim 2, wherein (2S)-12-norziza-6(13)-en-2-yl acetate is present in an amount such that the weight ratio of (2R)-12-norziza-6(13)-en-2-yl acetate to (2S)-12-norziza-6(13)-en-2-yl acetate [(R) (S)] is greater than 1.2.

5. A method for synthesizing the composition of claim 3 containing (2R)-12-norziza-6(13)-en-2-yl acetate in the absence of (2S)-12-norziza-6(13)-en-2-yl acetate, comprising: reducing khusimone in the presence of a reducing agent and an organic solvent to form 12-norziza-6(13)-en-2-ol, and acetylating the 12-norziza-6(13)-en-2-ol obtained in the reducing step in the presence of an organic solvent to form (2R)-12-norziza-6(13)-en-2-yl acetate.

6. The method of claim 5, wherein the reducing agent is selected from the group consisting of lithium aluminum hydride (LiAlH.sub.4), DiBAH (diisobutylaluminum hydride), sodium borohydride (NaBH.sub.4), lithium borohydride (NaLiH.sub.4) and potassium borohydride (KBH.sub.4).

7. The method of claim 5, wherein the molar ratio between the reducing agent (RA) and the khusimone (K) is between 0.5 and 5.

8. The method of claim 5, wherein the organic solvent is selected from the group consisting of methanol (MeOH), ethanol, propanol, isopropanol, n-butanol, sec-butanol, isobutanol, t-butanol, tetrahydrofuran (THF), 1,4-dioxane, dimethylsulfoxide (DMSO), acetonitrile, and mixtures in all proportions of these solvents.

9. The method of claim 5, wherein said step of acetylating 12-norziza-6(13)-en-2-ol is carried out by reacting the 12-norziza-6(13)-en-2-ol with an acetylating agent (Ac) in the presence of a base and a nucleophilic catalyst in an aprotic solvent.

10. The method of claim 9, wherein the acetylating agent (Ac) is selected from the group consisting of acetic anhydride, acetic acid, and acetyl chloride.

11. The method of claim 10, wherein, in said acetylating step, the molar ratio [(Ac)/(Z)] between the acetylating agent (Ac) and the 12-norziza-6(13)-en-2-ol (Z) is between 1 and 5.

12. The method of claim 9, wherein the organic base is selected from the group consisting of N,N-diisopropylethylamine (DIPEA), triethylamine (Et.sub.3N) and pyridine.

13. The method of claim 12, wherein the acetylation step is carried out with a molar ratio [(OB)/(Z)] between the organic base (OB) and the 12-norziza-6(13)-en-2-ol (Z) of 0.1 to 5.

14. The method of claim 9, wherein the nucleophilic catalyst is selected from the group consisting of 4-(N,N-dimethylamino)pyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and N,N-dicyclohexylcarbodiimide (DCC).

15. The method of claim 14, wherein the step of acetylating 12-norziza-6(13)-en-2-ol is carried out with a molar ratio [(NC)/(Z)] between the nucleophilic catalyst (NC) and the 12-norziza-6(13)-en-2-ol (Z) of 0.01 to 10.

16. The method of claim 9, wherein the aprotic solvent is selected from the group consisting of n-hexane, cyclohexane, 1,4-dioxane, dichloromethane (DCM), carbon tetrachloride (CCl.sub.4), benzene, trichloroethylene (Cl.sub.2CCHCl), tetrachloroethylene (Cl.sub.2CCCl.sub.2), toluene, carbon disulfide (CS.sub.2) diethyl ether (Et.sub.2O), chloroform (CHCl.sub.3), bromobenzene (PhBr), chlorobenzene (PhCl), ethyl acetate (AcOEt), dimethyl ether (DME), tetrahydrofuran (THF), 1,1-dichloroethane (C.sub.2H.sub.4Cl.sub.2), 1,2-dichloroethane (DCE), pyridine, butanone, acetone, acetic anhydride (Ac.sub.2O), tetramethylurea ((Me.sub.2N).sub.2CO), benzonitrile (PhCN), propionitrile (CH.sub.3CH.sub.2CN), hexamethylphosphoramide (HMPA), nitrobenzene (PhNO.sub.2), nitromethane (MeNO.sub.2), dimethylformamide (DMF), acetonitrile (MeCN), sulfolane, dimethylsulfoxide (DMSO), formamide (HCONH.sub.2), N-methylformamide (NMF), N-methylacetamide (CH.sub.3CONHMe), and acetic acid.

17. A fragrance agent comprising (2R)-12-norziza-6(13)-en-2-yl acetate, wherein said (2R)-12-norziza-6(13)-en-2-yl acetate is present in the absence of (2S)-12-norziza-6(13)en-2-yl, or in the presence of (2S)-12-norziza-6(13)-en-2-yl, in a weight ratio of (2R)-12-norziza-6(13)-en-2-yl acetate to (2S)-12-norziza-6(13)-en-2-yl acetate (R/S) greater than 1.2.

18. In a perfume, an eau de partum, an eau de toilette, a hygiene product, a cosmetic, a soap, a detergent or a candle having a fragrance agent therein, the improvement wherein said fragrance agent comprises (2R)-12-norziza-6(13)-en-2-yl acetate.

19. The perfume, eau de partum, eau de toilette, hygiene product, cosmetic, soap, detergent or candle according to claim 18, wherein the (2R)-12-norziza-6(13)-en-2-yl acetate is present in the absence of any (2S)-12-norziza-6(13)-en-2-yl form, or is present in the presence of (2S)-12norziza-6(13)-en-2-yl, in a weight ratio of (2R)-12-norziza-6(13)-en-2-yl acetate to (2S)-12-norziza-6(13)-en-2-yl acetate (R/S) greater than 1.2.

Description

EXAMPLES

Example 1: Synthesis of (2R)-12-norziza-6(13)-en-2-yl acetate from khusimone

Step 1: Synthesis of 12-norziza-6(13)-en-2-ol from khusimone

(1) In a flask, 3 mmol of khusimone are added in the presence of 6 mmol of sodium borohydride in 30 mL of ethanol to obtain a khusimone concentration 0.1M, at room temperature for 2 h. The solvent is then evaporated in vacuum and 10 mL of dichloromethane are added to the reaction mixture. Next, 10 mL of 1N hydrochloric acid are added. Following decantation, the organic phase is recovered and washed with brine, and finally dried over magnesium sulfate. After solvent evaporation, the product is obtained as a colorless oil with a 97% yield.

Step 2: synthesis of (2R)-12-norziza-6(13)-en-2-yl acetate from 12-norziza-6(13)-en-2-ol

(2) The product obtained in step 1 is mixed with acetic anhydride (2 equivalents), triethylamine (1.2 equivalents) and 4-dimethylaminopyridine (0.1 equivalents) in 10 mL of dichloromethane at room temperature for 2 h. The reaction mixture was washed with a 0.1 N hydrochloric acid solution, then with a saturated solution of sodium bicarbonate, and finally with brine. After drying over magnesium sulfate and solvent evaporation, the product is obtained as a colorless oil which crystallizes spontaneously. The reaction yield increases to 83% for (2R)-12-norziza-6(13)-en-2-yl acetate, with a purity of 98.5%.

(3) The result of this synthesis is shown in FIG. 1, appended, wherein can be seen the chromatogram obtained by gas chromatography of the product obtained at the end of the 2 synthesis steps, shown at the top of the FIGURE.

(4) Total removal of the starting material (khusimone) can be observed, as well as the presence of an important peak that reveals the presence of (2R)-12-norziza-6(13)-en-2-yl acetate, representing 98.5% by quantity of the total amount of (2R)- and (2S)-12-norziza-6(13)-en-2-yl acetate obtained. The presence of a minor peak can also be observed, which shows the presence of (2S)-12-norziza-6(13)-en-2-yl acetate and represents less than 1.5% by quantity of the total amount of (2R)- and (2S)-12-norziza-6(13)-en-2-yl acetate obtained.

(5) Identification of the different compounds was made by mass spectrometry, as well as by nuclear magnetic resonance after isolation of said compounds.