RU2420507C1 - Method of producing 3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1, having high anticonvulsant activity, through isomerisation of verbenol epoxide in the presence of cobalt-containing montmorillonite clay.

EFFECT: 1,5-fold increase in content of the desired compound in the reaction mixture.

1 cl, 2 ex, 1 tbl

Description

The invention relates to the field of chemistry of drugs, namely to a new method for producing 3-methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 1, which has high anticonvulsant activity [1 ].

Oxygen-containing substances with a para-menthane backbone are an important type of natural compounds in terms of physiological activity. For example, (+) - perilyl alcohol 2 showed significant anticancer activity on a number of tumors [2], and carveol 3 has antimicrobial and insecticidal activities [3, 4]. 3-Methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 1 is one of the most interesting substances with a para-menthane backbone.

There is only one known method for producing 3-methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 1, which we adopted as a prototype [1]. The essence of the method consists in maintaining the verbenol 4 epoxide on acid montmorillonite clay (ascanite-bentonite or K 10), which serves as a catalyst, at room temperature in the presence of CH ₂ Cl ₂ for 40-60 minutes, resulting in the formation of 3-methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 1 with a yield of 44-47% and other substances, mainly compounds 5 and 6 with a cyclopentane backbone (Scheme 1) [1, 5 , 6]. Further isolation of individual compound 1 was carried out using column chromatography.

A significant disadvantage of the known method for producing 3-methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 1 is its insufficiently high yield of less than 50%.

It should be noted that the use of other acid catalysts instead of montmorillonite clays does not lead to the preparation of compound 1 with acceptable selectivity. For example, only compound 5 was isolated in the presence of ZnBr ₂ , and the formation of diol 1 was not observed [7].

The objective of the invention is to provide an effective method for producing 3-methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 1.

The task of creating an effective method for the synthesis of 3-methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 1 is solved in the isomerization reactions of verbenol epoxide using cation-substituted montmorillonite clays containing as catalysts Co ⁺² .

The preparation of new catalysts was carried out by replacing the counterion in commercially available acidic montmorillonite clay K 10 (H ⁺ -K10) and natural acid-activated montmorillonite clay ascanite-bentonite (H ⁺ -AB) according to the previously described method [8]. Based on these montmorillonite clays, catalysts were synthesized containing a Co ²⁺ cation as a counterion (Example 1).

The catalysts obtained in Example 1 were used to obtain the target product as follows: a solution of verbenol 4 epoxide in CH ₂ Cl _{2 was} added to a suspension of the catalyst in CH ₂ Cl ₂ at room temperature, after aging for 40 min, the catalyst was filtered off, the filtrate was evaporated, and the residue was added a solution of the internal standard in ethyl acetate and analyzed by GLC / MS (Example 2).

Analysis of the reaction products of 3-methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 1 was carried out by gas chromatography-mass spectrometry using a Hewlett-Packard 5890 / II gas chromatograph with a quadrupole mass - spectrometer (HP MSD 5971) as a detector with the introduction of an internal standard (dicyclopentadiene). A 30 m HP-5 quartz column (copolymer of 5% diphenyl-95% dimethylsiloxane) with an inner diameter of 0.25 mm and a film thickness of the stationary phase of 0.25 μm was used. A change in the content of 3-methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 1 in the reaction mixture was judged by a change in the ratio in the chromatogram of the peak areas corresponding to compound 1 and the internal standard .

The studies showed (Example 2, table) that the use of Co ²⁺ -containing montmorillonite clays (Co ²⁺ -K10 and Co ²⁺ -AB) can significantly increase the content of 3-methyl-6- (prop- 1-en-2-yl) cyclohex-3-en-1,2-diol 1 in the reaction mixture compared to acid montmorillonite clays previously used in the prototype.

Isolation of individual compound 1 can be carried out, for example, using column chromatography in accordance with known methods [1, 5, 6].

The invention is illustrated by the following examples.

Example 1. Preparation of ion-exchange modifications of montmorillonite clays Co ²⁺ -K10 and Co ²⁺ -AB.

To 5.0 g of acid montmorillonite clay K 10 (Fluka) or natural acid montmorillonite clay Ascanite-bentonite (AB, obtained by acid activation of bentonite clays of the Askanskaya group of deposits, Georgia; corresponds to OST 113-12-86-82), 25 ml of 0.1 N Co solution (NO ₃ ) ₂ in distilled water, stirred for 2 hours, kept at room temperature for 22 hours, the aqueous layer was decanted. Again, 25 ml of a 0.1 N solution of Co (NO ₃ ) _{2 was} added to the precipitate, stirred for 2 hours, kept at room temperature for 22 hours, the aqueous layer was decanted; then the indicated operation was repeated 3 more times. The precipitate was filtered off, washed with distilled water (3 × 50 ml), dried for 3 hours at 105 ° C. Catalysts Co ²⁺ -K10 and Co ²⁺ -AB were prepared.

Example 2. Obtaining 3-methyl - 6 - (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 1 in the presence of ion-exchange clays, general procedure.

To a suspension of 0.100 g of the corresponding clays, previously dried for 3 hours at 100 ° C in 1 mL of CH ₂ Cl ₂ was added at 20 ° C solution of 0.050 g of epoxide (-) - cis-verbenol 4 in 1 mL of CH ₂ Cl ₂ and stirred at this temperature for 40 minutes Added 3 ml of diethyl ether, stirred for 10 minutes, the catalyst was filtered off, the solvent was distilled off. To the residue were added 2.0 ml of ethyl acetate and 0.5 ml of a 40% solution of dicyclopentadiene (internal standard) in ethyl acetate.

The reaction mixture was analyzed by chromatography-mass spectrometry. A qualitative analysis of the reaction products was carried out by comparing the retention indices (Kovacs indices) of the components and their complete mass spectra with the corresponding data for pure compounds. The change in the content of products in the reaction mixture was judged by the change in the ratio of the areas of chromatographic peaks corresponding to these compounds to the peak area of the internal standard.

The results of the reactions are presented in the table.

The above results demonstrate that the isomerization of verbenol 4 epoxide to synthesize 3-methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol 1 in the presence of a Co ²⁺ -containing montmorillonite clay Co ²⁺ -K10 provides an increase in the content of compound 1 in the reaction mixture by 1.5 times in comparison with the previously used catalyst H ⁺ -K10.

Information sources

1. Ilyina I.V., Bolkunov A.V., Dolgikh M.P., Volcho K.P., Tolstikova T.G., Salakhutdinov N.F. Anticonvulsant. Patent RU 2355390, 05.20.2009.

2. Wang G., Tang W., Bidigare R.R. Terpenoids as therapeutic drugs and pharmaceutical / Natural products. Drug discovery and therapeutic medicine. Eds. Zhang L., Demain A.L., Totowa: Humana Press, 2005, p. 201.

3. Sivropoulou A., Kokkini S., Lanaras T., Arsenakis M. Antimicrobial activity of mint essential oils. J. Agric. Food Chem., 43 (1995) 2384-2388.

4. Jang Y.-S., Yang Y.-C., Choi D.-S., Ahn Y.-J. Vapor Phase Toxicity of Marjoram Oil Compounds and Their Related Monoterpenoids to Blattella germanica (Orthoptera: Blattellidae). J. Agric. Food Chem., 53 (2005) 7892-7898.

5. Il'ina I.V., Volcho K.P., Korchagina D.V., Barkhash V.A., Salakhutdinov N.F. Reactions of Allyl Alcohols of the Pinane Series and of Their Epoxides in the Presence of Montmorillonite Clay. Helvetica Chimica Acta, 90 (2007) 353-368.

6. Ardashov O.V., Il'ina I.V., Korchagina D.V., Volcho K.P., Salakhutdinov N.F. Unusual α-hydroxyaldehyde with a cyclopentane framework from verbenol epoxide. Mendeleev Communications, 17 (2007) 303-305.

7. Amri H., El Gaied M.M., M'Hirsi M. Reaction of trimethylamine dihydrofluoride with simple epoxides and a-functional derivatives of a bicyclo [3.1.1] heptane monoterpene. J. Soc. Chim. Tunis, (1983) 25-32.

8. Toma S., Elecko P., Gazova J., Solcaniova E. Diels-Alder reactions on acryloylferrocene with 1-phenyl-1,3-butadien catalysed by homoionic forms of montmorillonite. Collect. Czech Chem. Commun. 52 (1987) 391-394.

Claims (1)

A method of producing 3-methyl-6- (prop-1-en-2-yl) cyclohex-3-en-1,2-diol by isomerization of verbenol epoxide on montmorillonite clays, characterized in that montmorillonite clays contain Co ²⁺ .