16a, 17a-cyclohexano-5a,6a-epoxypregn-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. Ibrahim-Quali. Synthesis of pentacyclic steroids. Steroids, 2008, 73, N 8, 775-97], condensed with the steroid skeleton in the 16a,17a-positions [Bioorgan.Khimia, 2005, V.31, P. l 15 and 227], and more particularly to a process for obtaining 16a,17a-cyclohexano-5a,6ct - epoxypregn-3 β-οΙ-20-one acetate (I):

The compound of the formula I is an intermediate in the synthesis of a highly efficient progestin, a 6a-methyl-16a,17a-cyclohexanoprogesterone.

It is known a unique process for obtaining a formula I compound with a high yield by interaction of 16a,17a-cyclohexanopregn-5-en-3P-ol-20-one acetate with 10% essential solution of monoperphthalic acid (2 molar equivalents) in chloroform [A.A. Akhrem, A.V. amernitsky, L.E. Kulikova, I.S. Levina. Synthesis of A ⁶ -6-substituted cyclohexano [Ι', 2'; 16a, 17a] progesterones, Izv. AN SSSR, ser. chem., 1978. Jfe 2,444-447]. It was described that this reaction resulted in the full disappearance of the initial 16a,17a-cyclohexanopregn-5- en-3p-ol-20-one acetate and, consequently, in the formation of 5a,6a-oxide I, a product of epoxidation. The process flows at high dilution for a long period, 24 hours under cooling and further for 48 hours at room temperature. The desired product yield was 95%. To prove the structure, only the ultimate analysis was used. However, a thorough analysis we carried out of the reaction product with NMR spectroscopy showed that with this reaction, when the initial olefin is completely converted, some amount (up to 30%) of an unwanted 5p,6P-epoxide was formed as well (see the comparative example 4). The disadvantages of the known process reside likewise in the performing epoxidation in a strongly diluted medium with the use of an explosive and inflammable diethyl ether, of an unstable peracid and for a long duration of the process. These conditions are not suitable while scaling up the process.

The aim of the present invention is to simplify the described process, to decrease the reaction volume and the duration of the process as well as to improve the specificity of the process for providing generation of the desired a-isomer. The targeted task is achieved by the proposed process for 16a, 17a- cyclohexano-5a,6a- e oxypregn-3p-ol-20-one acetate of the formula

by treating the 16a,17a-cyclohexanopregn-5-en-3p-ol-20-one acetate with an organic peracid in the medium of a polar organic solvent, a particular characteristic of which is that p- carbomethoxyperbenzoic acid is used as the organic peracid, and the process is carried out at the temperature of 25 - 30°C and at the molar ratio of 16a,17a-cyclohexanopregn-5-en-3p-ol- 20-one acetate : p-carbomethoxyperbenzoic acid 1 : 1.1 - 1.5.

Methylene chloride is preferably used as the organic solvent. P-carbomethoxyperbenzoic acid is used as a suspension in methylene chloride. The desired product contained in a solution is easily isolated after filtering the precipitate of p-carbomethoxyperbenzoic acid.

The yield of the desired product is 76-80%, which is confirmed by the data of the physicochemical analysis.

The technical result is the security and simplifying of the process and the improved specificity of the process for providing generation of an a-isomer, the desired product.

The advantages of the proposed process are as follows: a) use of an explosion-proof and fireproof p-carbomethoxyperbenzoic acid; b) carrying out the process at room temperature (25 - 30°C) without heating or cooling; c) shortening the reaction time to 1-2 hours; d) reducing the volume of the reaction mass; e) simplifying the process of the desired production recovery. 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 p-carbomethoxyperbenzoic acid is available and can be obtained with a high yield by oxidation of methyl-p-formylbenzoate with oxygen, initiated by ozone (0.5-1%) in a solution of tetrachloromethane [G.S. Bylina, G.A. Tolstikov, G.I. Rutman, P.N. Zernov, V.N. Odinokov, U.M.Djemilev, USSR Author's Certificate No 656130, Bulletin of Inventions No 15, p. 21 (1979)]. The initial compound for obtaining this peracid is a by-product of the industrial manufacture of monomethyl terephtalate. The peracid with the purity of 78-85% manufactured in this way represents a stable crystalline substance soluble in most of organic solvents and decomposed without explosion at 120°C. Literature contains the only publication on oxidation of some natural A ⁵ -steroids with p-carbomethoxyperbenzoic acid, where it is shown that, as a result, mixtures of isomeric epoxides were obtained, the stereospecifity of the epoxidation depending, together with other factors, on the structure of the used steroid olefin [G.S. Bylina, U.M. Djemilev, N.S. Vostrikov, G.A. Tolstikov, A.M. Moiseenkov, A.V. Semenovsky, S.S. Shavanov. Oxidation with p-carbomethoxyperbenzoic acid. 1. Stereochemistry of A ⁵ -steroids epoxidation].

The proposed invention satisfies the criterion "inventive level" since it was not evident that the use of this peracid for the class of pentaranes used in this invention could result in the preferable formation of the desired 5a,6 -epoxide.

The modification of the molar ratio of reagents lead to the preferred obtaining of the ct- isomeric oxide. This direction of the process was not evident, since the use of lower amount of peracid in the epoxidation of natural A ⁵ -steroids lead to a considerable amount of β-oxide (G.S. Bylina, U.M. Djemilev, N.S. Vostrikov, G.A. Tolstikov, A.M. Moiseenkov, A.V. Semenovsky, S.S. Shavanov. Oxidation with p-carbomethoxyperbenzoic acid. 1. Stereochemistry of A ⁵ -steroids epoxidation). Yet the use of a larger amount of peracid can lead to a considerable reduction of the yield of the a-oxide.

The invention satisfies the requirement of the "industrial applicability", since it can be used in the manufacture of an intermediate product for the synthesis of steroid hormones of the pregnane series that are valuable hormonal preparations used in medicine to treat hormonal disorders, miscarriage in pregnancy and as contraceptive components.

Example 1.

To the solution of 30 g (0.073 mol) of 16a,17oc-cyclohexanopregn-5-en-3p-ol-20-one acetate in 150 ml of dry methylene chloride under vigorous stirring a suspension of 19.33 g (1.12 molar equivalents) of 78% p-carbomethoxyperbenzoic acid in 150 ml of dry methylene chloride was rapidly added. The reaction mass was stirred for 2 h at room temperature (TCX control) after that, the precipitated deposit of p-carbomethoxyperbenzoic acid was filtered and thoroughly washed on a filter with methylene chloride. The filtrate was treated with 5% sodium bicarbonate solution, with water, and the solvent was eliminated under vacuum. The crystalline residue obtained was recrystallized from aqueous acetone. 23.73 g (76 %) of 16a,17a-cyclohexanopregn-5-en-3p-ol-20-one-acetate were obtained with the fusion point of 244-247°C. NMR Spectrum Ή (δ, m.d.): 0.62 (c 3 H, Me(18)); 1.08 (c, 3 H, Me(19)); 2.02 (c, 3 H, 3-OAc); 2.12 (c, 3 H, Me(21)); 2.90 (d, 1H, 6H, J 3.6 Hz); 4.97 (m, 1H, 3H). From the mother solution, after 3-fold separation of the desired product, the 16α,17α- cyclohexanopregn-5-en-3p-ol-20-one acetate, more hardly soluble, and after the recrystallization of the residue, the solvents being eliminated from the ether-hexane mixture, a desired product isomer, the 16a,17a-cyclohexano-5p,6p-epoxypregn-3p-ol-20-one acetate was recovered, with the fusion point of 166-168°C.

Example 2.

To the solution of 30 g (0.073 mol) of 16a,17a-cyclohexanopregn-5-en-3,20-dione acetate in 150 ml of dry methylene chloride under vigorous stirring a suspension of 33 g (2 molar equivalents) of 80.5% p-carbomethoxyperbenzoic acid in 200 ml of dry methylene chloride was rapidly added. The reaction mixture was stirred for 2 h at room temperature, after that, the precipitated deposit of p-carbomethoxyperbenzoic acid was filtered and washed on a filter with methylene chloride. After a treatment similar to that of the described in Example 1 , 23.8 g (76 %) of 16a,17a-cyclohexano-5a,6a-epoxypregn-3p-ol-20-one acetate were obtained. Example 3

To the solution of 30 g (0.073 mol) of 16a,17a-cyclohexanopregn-5-en-3,20-dione acetate in 150 ml of dry methylene chloride under vigorous stirring, a suspension of 33 g (2 molar equivalents) of 80.5% p-carbomethoxyperbenzoic acid in 200 ml of dry methylene chloride was rapidly added. The reaction mixture was stirred for 1 h at 30°C and treated similarly to the described above. 25.3 g (80 %) of 16a,17a-cyclohexano-5ct,6a-epoxypregn-3p-ol-20-one acetate were obtained.

Example 4 (comparative).

The solution of 30 g (0.073 mol) of 16a,17a-cyclohexanopregn-5-en-3,20-dione acetate in 250 ml of dry methylene chloride was cooled with ice, and 313 ml of essential solution of monoperphtalic acid (26.57 g (0.146 mol) of 100% peracid) were added under stirring. The reaction mixture was kept at room temperature for 48 h, the precipitated monophtalic acid was filtered out, after that it was treated with a saturated solution of Na ₂ C0 ₃ , washed with water and dried with Na ₂ SC>4. The solvents were eliminated under vacuum, and the crystalline residue obtained was recrystallized from the aqueous acetone. 17.1 g (55%) of 16α, 17a- cyclohexano-5a,6a-epoxypregn-3p-ol-20-one acetate of the formula I were obtained.

Additionally, 5.02 g of a product containing a considerable admixture of isomeric 5β,6β- epoxide, according to the NMR spectrum, were recovered.