The present invention relates to the chemistry of natural and physiologically active substances and especially, to a process for obtaining an intermediate product in the synthesis of steroid hormones of the pregnane series, containing an additional six-membered carbocycle [M. Ibrahim-Quali. Synthesis of pentacyclic steroids. Steroids, 2008, 73, N 8, 775-97], condensed with the steroid skeleton in the 16a,17a-positions [A.V. Kamernitsky, I.S.Levina. Pregna-O'- pentaranes. Progestins and antiprogestins. Bioorgan.Khimia, 2005, V.31, P.l 15 and 227], and more particularly to a process for obtaining 16a,17a-cyclohex-3',4'-enopregn-5-en-3P-ol-20- one acetate of the formula I:

The compound according to the formula I represents the key intermediate in the synthesis of a highly efficient progestin, the 6a-methyl-16a,17a-cyclohexano-progesterone.

It is known a unique process for obtaining a formula I compound by addition of a quintuple excess of 1,3-butadiene to 16-dehydropregnenolone acetate while heating the components at 140-150°C or at room temperature in the presence of anhydrous aluminum chloride in a sealed ampoule, in the medium of anhydrous methylene chloride [A.A. Akhrem, L.E. Kulikova, I.S. Levina, Yu.A. Titov. Process for obtaining pregnane derivatives with cyclohexene rings condensed in positions 16,17. USSR Author's Certificate No 273195, Bulletin of Inventions 1970, No 20; A.A. Akhrem, L.E. Kulikova, I.S. Levina, Yu.A. Titov. Synthesis of pentacyclic analogs of progesterone with an additional ring in positions 16,17. Izvestia AN SSSR, ser. chem., 1972, No 6, 1358-63]. The desired product is isolated by decomposition of the reaction mixture with aqueous solution of sodium bicarbonate. To carry out the process in a sealed ampoule complicates the technology of the desired product manufacture on a large scale. And what is more, when carrying out the process in the medium of methylene chloride, the decomposition of the reaction medium with the aqueous solution of sodium bicarbonate generates emulsions of the aqueous phase and of the methylene chloride difficult to separate, which complicates the process run.

The aim of the present invention is to simplify the technology for obtaining the compound of the formula I.

The targeted task is achieved by the proposed process for obtaining 16a,l 7a-cyc]ohex-3',4'- enopregn-5-en-3p-ol-20-one acetate by interaction of 16-dehydropregnenolone acetate with 1,3 -butadiene in the medium of an organic solvent in the presence of Lewis acid, the characteristics of the process according to the invention consisting in the process run at the molar ratio of 16-dehydropregnenolone acetate, 1,3-butadiene and of Lewis acid within 1 : 2 - 3: 0,2 -0,4, at the temperature of -10°C, the reaction mixture temperature being further brought to room temperature, the reaction mixture being passed through a sorbing agent layer, and the desired product isolated by known processes. The desired product yield is 80-85%. As the Lewis acid, mostly anhydrous aluminum chloride (AICI ₃ ) or titanium tetrachloride (TiCl ₄ ) are used.

As the organic solvent, mostly toluene or methylene chloride are used.

As the sorbing agent, mostly silica gel, aluminum oxide, celite are used.

The use of 2-3 molar equivalents of 1 ,3-butadiene and of 0.2-0.4 molar equivalents of Lewis acid (anhydrous AICI3, TiCl ₄ ) enables to avoid additional formation of impurities related to the products of butadiene thickening and the initial steroid resinification.

The reaction performed at the temperature of -10°C and the reaction mixture temperature brought to room temperature within a determined period allow to simplify the process, common equipment being used instead of a sealed ampoule.

Passing the reaction mixture through a sorbing agent without a preliminary water treatment allows to prevent the formation of stable emulsions at the decomposition of the reaction mixture with a solution of soda and water.

The technical result of the proposed invention is to simplify the process run thanks to the refusal to use the sealed equipment and to the treatment of the reaction mixture by passing it through a sorbing agent layer before isolating the desired product.

The invention corresponds to the criterion "novelty" since the known scientific and engineering literature and the patent literature do not describe the whole combination of features characterizing the proposed invention.

The invention satisfies the criterion "inventive level" since the fact to change the water treatment operation before isolating the desired product for an operation of passing the reaction mixture through a sorbing agent is not evident since for decomposing the obtained complex of the desired product with the Lewis acid, usually a solution of soda or water is required, see, for example [P.Yates, Ph.Eaton. Acceleration of the Diels-Alder reaction by Aluminum chloride. J.Am.Chem.Soc, 1960, 82, 4436-7; I. A. Favorskaya, E.M. Auvinen, G.V. Prilutskaya. Ethylene and acetylene ketones as dienophiles in the catalytic diene synthesis. ZhOrKh, 1970, 6, No 4, 720-23].

The process according to the invention is technologically effective since it does not require specific equipment, that is why it is industrially practicable.

The invention is illustrated with the following examples that do not limit its scope.

Example 1. To the suspension of 20 g (56 mmol) of 16-dehydropregnenolone acetate and of 1.6 g (12 mmol) of anhydrous AICI3 in 80 ml of methylene chloride under stirring and at - 10°C, 10 ml (112 mmol) of 1,3 -butadiene are added, the stirring being continued for 3 h. After that, cooling is stopped, the reaction mass temperature is allowed to rise up to room temperature at which it is maintained for 6 h more (TCX control). The reaction mixture is passed through a layer of silica gel, a sorbing agent. The sorbing agent is washed with toluene and finally with chloroform. The joint eluates are concentrated by evaporation, petroleum ether is added to the obtained residue and the crystalline deposit is filtered. 19.7 g (85.8%) of 16a,17a-cyclohex-3',4'-enopregn-5-en-3 -ol-20-one acetate are obtained with the melting point of 166-8°C (acetone-hexane).

NMR spectrum 1H (δ, m.d.): 0.72 (c 3 H, Me(18)); 1.01 (c, 3 H, Me(19)); 2.02 (c, 3 H, 3- OAc); 2.15 (c, 3 H, Me(21)); 3.10 (m, 1H,16H); 4.60 (m, 1H, 3H); 5.38(m, 1H,6H); 5.80 (m, 2H, 3'- and 4'-H).

Example 2. To the suspension of 10 g (28 mmol) of 16-dehydropregnenolone acetate and of 1.52 g (11.4 mmol) of anhydrous AICI3 in 40 ml of methylene chloride under stirring and at - 10°C, 9 ml (140 mmol) of 1,3 -butadiene are added, the stirring being continued for 3 h. After that, cooling is stopped, the reaction mass temperature is allowed to rise up to room temperature at which it is maintained for 6 h more (TCX control). After a treatment, similar to the described in the Example 1, 9.2 g (80.0 %) of compound I were obtained.

Example 3. To the suspension of 20 g (56 mmol) of 16-dehydropregnenolone acetate and of 1.6 g (12 mmol) of anhydrous AICI3 in 150 ml of toluene under stirring and at -10°C, 12.5 ml (140 mmol) of 1 ,3-butadiene are added, the stirring being continued for 3 h. After that, cooling is stopped, the reaction mass temperature is allowed to rise up to room temperature at which it is maintained for 10 h more (TCX control). After a treatment, similar to the described in the Example 1 , 19 g (82.7 %) of compound I were obtained. Example 4. To the suspension of 10 g (28 mmol) of 16-dehydropregnenolone acetate and of 0.8 g (6 mmol) of anhydrous AICI3 in 80 ml of toluene under stirring and at -10°C, 5.4 ml (84 mmol) of 1,3-butadiene are added, the stirring being continued for 3 h. After that, cooling is stopped, the reaction mass temperature is allowed to rise up to room temperature at which it is maintained for 10 h more (TCX control). After a treatment, similar to the described in the Example 2, 9.2 g (80 %) of compound I were obtained.

Example 5. To the suspension of 10 g (28 mmol) of 16-dehydropregnenolone acetate and of 1.25 g (12 mmol) of TiCh _. in 40 ml of methylene chloride under stirring and at -10°C, 5.4 ml (84 mmol) of 1,3-butadiene are added, the stirring being continued for 10 h. After that, cooling is stopped, the reaction mass temperature is allowed to rise up to room temperature at which it is maintained for 10 h more (TCX control). After a treatment, similar to the described in the Example 1, 9.1 g (79.2 %) of compound I were obtained.

Example 6. To the suspension of 10 g (28 mmol) of 16-dehydropregnenolone acetate and of 1.25 g (12 mmol) of TiCl ₄ in 80 ml of toluene under stirring and at -10°C, 5.4 ml (84 mmol) of 1,3-butadiene are added, the stirring being continued for 3 h. After that, cooling is stopped, the reaction mass temperature is allowed to rise up to room temperature at which it is maintained for 10 h more (TCX control). After a treatment, similar to the described in the Example 1 , 9.0 g (78.5 %) of compound I were obtained.

Thus the proposed process enables to simplify the obtaining of an intermediate product in the synthesis of steroid hormones of the pregnane series thanks to the refusal to carry out the process in a sealed equipment, which makes it economically advantageous.