RU2566366C1 - METHOD OF PRODUCING 6-METHYLENO-16α,17α-CYCLOHEXANOPREGN-4-ENE-3,20-DIONE - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 6-methyleno-16α,17α-cyclohexanopregn-4-ene-3,20-dione of formula (I)

which is an immediate precursor in synthesis of high-efficiency progestin - 6α-methyl-16α,17α-cyclohexano-progesterone. The method includes reacting 16α,17α-cyclohexanopregn-4-ene-3,20-dione with trimethyl orthoformate in a methanol medium or with triethyl orthoformate in an ethanol medium in the presence of para-toluene sulphonic acid at room temperature, and treating the obtained reaction mass containing the corresponding 3,5-dienol ether with N-methylaniline and 37% aqueous formaldehyde solution, holding the reaction mixture at 35-40°C, pouring into water cooled to 8-10°C, which contains sodium hydroxide, followed by extraction of the obtained isomeric mixture of 6α- and 6β-isomers of an (N-methyl-N-phenylaminomethyl)-derivative and treatment thereof with concentrated hydrochloric acid at room temperature.

EFFECT: effective protection of an authentic electronic image, high output of the end product, conducting the process in mild conditions, easy extraction of intermediate and end products.

2 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 pregnane series steroid hormones 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 at 16α, 17α-positions [A.V. Kamernitsky, I.S. Levin. Pregna-D′-pentarans. Progestins and antiprogestins. Bioorgan. Chemistry, 2005, v. 31, p. 115 and 227], and in particular to a method for producing 6-methylene-16α, 17α-cyclohexanopregn-4-en-3,20-dione of the formula:

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

A single method is known for preparing a compound of formula I by direct γ-methyleneation of a compound of formula II, i.e. the introduction of a methylidene group at the 6-position of the steroid molecule by condensation of a conjugated ketone II with a formaldehyde derivative (formaldehyde diethyl acetal) in the presence of phosphorus oxychloride and sodium acetate in a solution of a chlorinated hydrocarbon [I.S. Levina, A.V. Kamernitsky. Synthesis of 6α-methyl-16α, 17α-cyclohexanoprogesterone via γ-methyleneation of 16α, 17α-cyclohexanopregn-4-ene-3,20-dione (II). Izv. USSR Academy of Sciences, ser. Chem., 1997, No. 6, 1234-35]. The yield of the target product does not exceed 55%.

This method has a number of significant drawbacks that do not allow it to be used on an industrial scale, namely, rather stringent conditions for the reaction (prolonged boiling of the reaction mixture), the need for chromatographic purification of the reaction product, and insufficiently high yield of the target product.

The objective of the present invention is to increase the yield of 6-methylene-16α, 17α-cyclohexanopregn-4-ene-3,20-dione of the formula I and the simplification of the technology for its preparation.

The problem is achieved by the proposed method for producing 6-methylene-16α, 17α-cyclohexanopregn-4-ene-3,20-dione of formula I by reacting 16α, 17α-cyclohexanopregn-4-ene-3,20-dione of formula II with trimethylorthoformate (CH (OMe) ₃ ) in methanol or with triethylorthoformate (CH (OEt) ₃ ) in ethanol in the presence of para-toluenesulfonic acid (p-TsOH) at room temperature and the resulting reaction mass containing the corresponding 3,5-dienol ether of the formula :

where R = Me or Et, is treated with N-methylaniline and a 37% aqueous solution of formaldehyde, the reaction mixture is kept at 35-40 ° С, poured into water containing sodium hydroxide cooled to a temperature of 8-10 ° С, followed by isolation of the obtained in this isomeric mixture of 6α- and 6β-isomers (N-methyl-N-phenylaminomethyl) -derivative of the formula:

and treating it with concentrated hydrochloric acid at room temperature, followed by isolation of the desired product I.

The process proceeds as follows:

a) CH (OMe) ₃ or CH (OEt) ₃ , MeOH or EtOH, p-TsOH, 1 h; N-methylanaline; HCNO; b) HCl.

The total yield of target product I is 85%.

A distinctive feature of the method is the first stage of enolization of 4-dehydro-3-oxosteroid II and the second stage of aminomethylation of 3,5-dienol ether III with an aqueous solution of formaldehyde and N-methylaniline with the formation of N, N-disubstituted 6-aminomethyl derivative IV and further isolation of the target product I without further purification with quantitative yield.

The technical result of the proposed method is to increase the yield of the target product up to 85%, the implementation of the process under mild conditions (no elevated temperature is required), ease of isolation of the intermediate and the target products (chromatographic separation of the resulting compounds is not required).

In the known scientific, technical and patent literature there is no complete set of features characterizing the invention.

From the prior art it was not obvious that the claimed sequence of stages for this class of steroids - pentacyclic steroids - will proceed under mild conditions and with a high yield, since the presence of an additional ring D ′ could make certain changes during the process.

The invention can be used in the production of an intermediate product in the synthesis of steroid hormones of the pregnane series, which are valuable hormonal drugs used in medicine for the treatment of hormonal dysfunctions, miscarriage during pregnancy and as components of contraceptives.

The invention is illustrated by the following examples.

Example 1

A. To a suspension of 4 g of conjugated ketone II in a mixture of 40 ml of trimethylorthoformate (CH (OMe) ₃ ) and 80 ml of anhydrous methanol, 200 mg of para-toluenesulfonic acid are added. The reaction mass (suspension) is stirred at room temperature for 30 minutes. At the end of the reaction, 9.2 ml of N-methylaniline (color change) and 1 ml of a 37% aqueous formaldehyde solution are added to the reaction mass containing 3,5-dienol ether III (R = Me). The suspension is heated to a temperature of ~ 40 ° C, maintained at this temperature for 1.5 hours, after which the solution is poured into water (120 ml) cooled to 8-10 ° C, containing 1.2 g of NaOH, and stirred at the same temperature in within 30 minutes. The precipitate is filtered off, washed with water until neutral. 5.25 g of a mixture of the 6α and 6β isomers of the (N-methyl-N-phenylaminomethyl) derivative IV are obtained (yield 98%).

B. To a suspension of 3.9 g of a mixture of isomers IV in 50 ml of acetone, 2.8 ml of 32% hydrochloric acid are added dropwise. The reaction mass (solution) is kept at room temperature for 30 minutes. At the end of the reaction, the reaction mass is diluted with 100 ml of water and incubated for 30 minutes at room temperature. The precipitate is filtered off, washed first with 50 ml of a mixture of acetone-water (1: 2), then with water until neutral and dried in air. Obtain 3.43 g of the crystalline target 6-methylene pentaran I. The precipitate is dissolved in methylene chloride and filtered through a 20-fold amount of silica gel. The silica gel was washed with methylene chloride, the filtrate was evaporated to dryness, and a crystalline residue was obtained of the desired 6-methylene-16α, 17α-cyclohexanopregn-4-en-3,20-dione I (2.74 g, 90%). Mp 181-184 ° C (from a mixture of isopropyl alcohol-water). [α] _D +144 (from 1.30). Mass spectrum: found: m / z 391.2594 [M + Na] ⁺ . C ₂₆ H ₃₆ O ₂ . Calculated: M = 380.2715. ¹ H NMR spectrum (δ, ppm): 0.70 s (3 H, 18-CH ₃ ), 1.10 s (3 H, 19-CH ₃ ), 2.15 (3 H, 21- CH ₃ ), 2.98 m (1 H, H 16), 4.94-5.06 d (2 H, C 6 = CH ₂ ), 5.92 s (1 H, H 4).

Example 2. Analogously to example 1 in stages A and B, from 1 g (2.7 mmol) of conjugated ketone II, 20 ml of CH (OEt) ₃ and 4 ml of absolute ethanol and 200 mg of p-toluenesulfonic acid, 0.87 g is obtained (85%) 6-methylene-16α, 17α-cyclohexanopregn-4-en-3,20-dione I.

Claims (1)

The method of obtaining 6-methylene-16α, 17α-cyclohexanopregn-4-en-3,20-dione of the formula:

of 16α, 17α-cyclohexanopregn-4-en-3,20-dione of the formula:

characterized in that the 16α, 17α-cyclohexanopregn-4-en-3,20-dione of formula II is reacted with trimethylorthoformate in methanol or with triethyl orthoformate in ethanol in the presence of p-toluenesulfonic acid at room temperature and the resulting reaction mass containing the corresponding 3,5-dienol ether of the formula:

where R = Me or Et, is treated with метил-methylaniline and a 37% aqueous solution of formaldehyde, the reaction mixture is kept at 35-40 ° С, poured into water containing sodium hydroxide cooled to a temperature of 8-10 ° С, followed by isolation of the obtained in this isomeric mixture of 6α- and 6β-isomers (N-methyl-N-phenylaminomethyl) -derivative of the formula:

and treating it with concentrated hydrochloric acid at room temperature.