16a, 17a-cyclohex-3',4'-enopregn-5 -en-3 β-οΙ-20-one acetate

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. Ibra- him-Quali. Synthesis of pentacyclic steroids. Steroids, 2008, 73, N 8, 775-97], condensed with the steroid skeleton in the 16a,17ot-positions [A.V. Kamernitsky, I.S.Levina. Pregna-D ¹ - 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. Kulik- ova, 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 and lowers the yield of the desired product.

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,17a-cyclohex-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 and by treating the reaction mixture with a solution of soda and water followed by isolation of the desired product, the characteristics of the process according to the invention consisting in the use of toluene, as the organic solvent, and in that the process is carried out 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 desired product yield is 80%.

As the Lewis acid, mostly anhydrous aluminum chloride (AICI3) or titanium tetrachloride (T1CI ₄ ) 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 resinifi cation.

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.

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 fact that the toluene solvent applied enables to prevent formation of stable emulsions at the decomposition of the reaction mixture.

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 fact that toluene enables to prevent formation of stable emulsions at the decomposition of the reaction mixture was not evident and did not result in an obvious way for specialists from the art. Thus, the invention satisfies the criterion "inventive level".

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 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). The reaction mixture is treated with 50 ml of saturated solution of Na ₂ C03, the organic layer is separated and washed with water, the aqueous residue is extracted with toluene. The joint organic layers are washed with water, dried at MgSC , and the most of the solvent is eliminated. To the residue obtained, petroleum ether is added and the precipitated deposit is filtered, washed with petroleum ether on a filter and dried on air. It gives 18.4 g (80%) of 16a,17a-cyclohex-3',4'-enopregn-5-en-3p-ol-20-one acetate with the melting point of 166-8°C (acetone-hexane).

NMR spectrum Ή (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 solution of 10 g (28 mmol) of 16-dehydropregnenolone acetate and of 0.8 ml 1.25 ml (12 mmol) of T1CI4 in 40 ml of toluene under stirring and at -10°C, 12.5 ml 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 and left overnight (TCX control). After a treatment, similar to the above described, 9.1 g (79.2 %) of 16a,17a-cyclohex-3',4'-enopregn-5-en-3p-ol-20-one acetate were obtained.

Example 3. To the suspension of 10 g (28 mmol) of 16-dehydropregnenolone-acetate and of 1.25 ml (12 mmol) of T1CI4 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 and left overnight (TCX control). After a treatment, similar to that of the example 1, 9.0 g (78.5%) of compound I were obtained.