RU2480476C1 - METHOD OF PRODUCING 16α,17α-CYCLOHEX-3',4'-ENOPREGN-5-EN-3β-OL-20-ONE ACETATE - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: goal is achieved using the described method of producing 16α,17α-cyclohex-3',4,-enopregn-5-en-3β-ol-20-one acetate by reacting 16-dehydropregnenolone with 1,3-butadiene in the medium of an organic solvent - toluene, at temperature of -10°C n the presence of a Lewis acid and treating the reaction mixture with a solution of soda and water, followed by separation of the end product using existing methods.

EFFECT: simple method of producing an intermediate product in synthesis of pregnane steroid hormones by not conducting the process in a sealed apparatus.

1 cl, 3 ex

Description

The invention relates to the field of chemistry of natural and physiologically active substances, and in particular to a method for producing 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 a steroid skeleton in 16α, 17α-positions [A.V. Kamernitsky, I.S. Levina. Pregna-D'-Pentarans. Progestins and antiprogestins. Bioorgan. chemistry, 2005. T.31, C.115 and 227], namely, to a method for producing acetate 16α, 17α-cyclohex-3 ', 4'-enopregn-5-en-3β-ol-20-one of the formula I:

The compound of formula I is a key intermediate in the synthesis of highly effective progestin - 6α-methyl-16α, 17α-cyclohexano-progesterone.

There is only one known method for producing a compound of formula I by attaching a 5-fold excess of 1,3-butadiene to 16-dehydropregnenolone acetate by heating the components at 140-150 ° C or at room temperature in the presence of anhydrous aluminum chloride in a sealed ampoule in anhydrous methylene chloride medium [A .A.Akhrem, L.E. Kulikova, I.S. Levina, and Yu.A. Titov. A method of producing derivatives of pregnane with cyclohexene rings condensed in positions 16.17. USSR Copyright Certificate No. 273195, Bull. fig. 1970, No. 20; A.A. Akhrem, L.E. Kulikova, I.S. Levina, and Yu.A. Titov. Synthesis of penta-cyclic progesterone analogues with an additional ring at positions 16.17. Izv. USSR Academy of Sciences, ser. Chem., 1972, No. 6, 1358-63]. The selection of the target product is carried out by decomposition of the reaction mixture with an aqueous solution of sodium bicarbonate. The process in a sealed ampoule complicates the technology of production of the target product on a large scale. In addition, when carrying out the process in an environment of methylene chloride during decomposition of the reaction mixture with an aqueous solution of sodium bicarbonate, difficult to separate emulsions of the aqueous phase and methylene chloride are formed, which complicates the process and reduces the yield of the target product.

The objective of the present invention is to simplify the technology for obtaining the compounds of formula I.

The problem is achieved by the proposed method for producing 16α, 17α-cyclohex-3 ', 4'-enopregn-5-en-3β-ol-20-one acetate of formula I by reacting 16-dehydropregnenolone acetate with 1,3-butadiene in an organic solvent in the presence of a Lewis acid and treatment of the reaction mixture with a solution of soda and water, followed by isolation of the target product, the distinguishing feature of which, according to the invention, is that toluene is used as an organic solvent and the process is carried out at a molar ratio of acetate 16- egidropregnenolona 1,3-butadiene and a Lewis acid is 1: 2-3: 0.2-0.4 at a temperature of -10 ° C, followed by adjusting the temperature of the reaction mixture to room temperature.

The yield of the target product is 80%.

Anhydrous aluminum chloride (AlCl ₃ ) or titanium tetrachloride (TiCl ₄ ) is predominantly used as the Lewis acid.

Use 2-3 mol / equiv. 1,3-butadiene and 0.2-0.4 mol / equiv. Lewis acid (anhydrous AlCl ₃ , TiCl ₄ ) avoids the additional formation of impurities associated with the products of compaction of butadiene and resinification of the original steroid.

Carrying out the reaction at a temperature of -10 ° C with bringing the temperature of the reaction mixture to room temperature over a period of time makes it possible to simplify the process, since in this case conventional equipment is used, rather than a sealed ampoule.

The technical result of the invention consists in simplifying the process, due to the failure of the process in sealed equipment, and also due to the fact that the used toluene solvent avoids the formation of stable emulsions during decomposition of the reaction mixture.

The invention meets the criterion of "novelty", as in the well-known scientific, technical and patent literature there is no complete set of features characterizing the invention.

The fact that toluene avoids the formation of stable emulsions upon decomposition of the reaction mixture was not obvious and did not follow explicitly for a person skilled in the art. Thus, the invention meets the criterion of "inventive step".

The proposed method is technological, since it does not require specific equipment and therefore is industrially applicable.

The invention is illustrated by the following examples, not limiting its scope.

Example 1. To a stirred suspension of 20 g (56 mmol) of 16-dehydropregnenolone acetate and 1.6 g (12 mmol) bezv. AlCl ₃ in 150 ml of toluene, 12.5 ml (140 mmol) of 1,3-butadiene is added at -10 ° C and stirring is continued for 3 hours. Cooling is then removed, the temperature of the reaction mixture is allowed to rise to room temperature and left to stand for another 10 hours (control TLC). The reaction mixture is treated with 50 ml of sat. Na ₂ CO ₃ solution, the organic layer is separated and washed with water, the aqueous layer is extracted with toluene. The combined organic layers were washed with water, dried with MgSO ₄ and most of the solvent was removed. Petroleum ether was added to the obtained residue, and the precipitate formed was filtered off, washed on a filter with petroleum ether, and dried in air. Received 18.4 g (80%) of acetate 16α, 17α-cyclohex-3 ', 4'-enopregn-5-en-3β-ol-20-one I with so pl. 166-8 ° C (acetone-hexane).

¹ H NMR Spectrum (δ, ppm): 0.72 (s 3H, Me (18)); 1.01 (s, 3H, Me (19)); 2.02 (s, 3H, 3-OAc); 2.15 (s, 3H, 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 a stirred solution of 10 g (28 mmol) of 16-dehydropregnenolone acetate and 0.8 ml of 1.25 ml (12 mmol) of TiCl ₄ in 40 ml of toluene, 12.5 ml of 1,3-butadiene are added at -10 ° C and stirring is continued for 3 h. Then remove the cooling, allow the temperature of the reaction mass to rise to room temperature and leave to stand another 10 hours and leave overnight (TLC control). After processing similar to that described in Example 1, 9.1 g (79.2%) of 16α, 17α-cyclohex-3 ′, 4′-enopregn-5-en-3β-ol-20-one I acetate was obtained.

Example 3. To a stirred suspension of 10 g (28 mmol) of 16-dehydropregnenolone acetate and 1.25 ml (12 mmol) of TiCl ₄ in 80 ml of toluene are added at -10 ° C 5.4 ml (84 mmol) of 1,3-butadiene and stirring is continued in for 3 hours. Then cooling is removed, the temperature of the reaction mixture is allowed to rise to room temperature and left to stand for another 10 hours (TLC control). After processing, similar to example 1, receive 9.0 g (78.5%) of compound I.

Claims (1)

The method of producing acetate 16α, 17α-cyclohex-3 ', 4'-enopregn-5-en-3β-ol-20-one of the formula 1:

by reacting 16-dehydropregnenolone acetate with 1,3-butadiene in an organic solvent in the presence of a Lewis acid and treating the reaction mixture with a soda solution and water, followed by isolation of the target product, characterized in that toluene is used as an organic solvent and the process is carried out in a molar ratio 16-dehydropregnenolone 1,3-butadiene acetate and Lewis acid equal to 1: 2-3: 0.2-0.4 at a temperature of -10 ° C, followed by bringing the temperature of the reaction mixture to room temperature.