DE2438424A1 - Equilenin and derivs.prepn. - by aromatizing steroid 1,3,5(10), 7-tetraenes with sodium dihydro-bis(2-methoxy-ethoxy)-aluminate - Google Patents

Abstract

Equilenin and derivs. of formula (I): (where R1 is H or CH3; and R2 is O, beta-OH, alpha-H, or a protected oxygen group) are prepd. by reacting 1,3,5(10),7-tetraenes of formula (II) with sodium dihydro-bis(2-methoxyethoxy) aluminate (III) and opt. re-oxidizing a 17-oxo group reduced during the reaction or eliminating the protecting group from a protected 17-oxo group. (I) are useful as intermediates for pharmaceutically active steroids and themselves are useful as oestrogens in human and veterinary medicine.

Description

Process for the production of equilenin and equilenin derivatives The invention relates to a process for the production of equilenin and equilenin derivatives of the general formula I where R1 is a hydrogen atom or a methyl group and R2 is an oxygen atom, a β-hydroxy-α-hydrogen or a protected oxygen group, characterized in that equilin or an equilin derivative of the general formula II Cii) where R1 and R2 have the meaning given in formula 1, with sodium dihydrobis (2-methoxyethoxy) aluminate £ NaAlH2 (002H4-OCH3); and, if appropriate, re-oxidizes a 17-ketone reduced during the reaction or the protective group of a protected 17-ketone.

Equilenin and equilenin derivatives are important parent steroids for Manufacture pharmaceutically active steroid substances and are themselves called estrogenic used in human and veterinary medicine.

For the production of equilenin and equilenin derivatives are already suggested a number of procedures. After this process, the second double bond becomes in the B-ring of the steroid structure, for example by bromination (Tetrahedron 26 (1970) 1917) or epoxidizing (U.S. Patent 3,647,831) the 7,8 double bond. The proceedings by reaction with oxidizing agents have the disadvantage that the oxidation is easy Goes beyond what is desired if, for example, one does not respond in time breaks off. In addition, you have to keep exactly at low temperatures, which are usually low work.

It has now been found that the introduction of the second double bond in ring B, i.e. the aromatization of ring B, also with sodium dihydro-bis (2-methoxyethoxy) -aluminate, one Reducing agent, succeeds. The feasibility of the invention Process with a reducing agent is surprising because the result is dehydration of the steroid molecule occurs.

When using the 17-ketones as starting steroids of the general Formula II also finds the expected reduction to the corresponding ones at the same time 17ß-hydroxysteroids instead.

The method according to the invention is preferably carried out in a sole: hydrogen, such as benzene or toluene, carried out at boiling temperature. The work-up takes place by decomposition of the reaction mixture and precipitation of the reaction product with a Alcohol and / or water.

Particularly suitable alcohols are methanol and ethanol.

A 17-keto group present in the starting steroid becomes under the conditions of the process according to the invention reduced to the 17β-hydroxyl group. Possibly can be a reduced 17-eeto group in the usual way, for example with chromic acid, be re-oxidized. A 17-keto group protected, for example by ketal formation is not attacked in the method according to the invention. The 17-keto group can after the reaction according to the invention by ketal cleavage with an aqueous acid to be released again.

The following examples are intended to elaborate on the method of the invention explain.

Example 1 2.00 g of the equilin or the corresponding equilin derivative are suspended in 30 ml of toluene. At room temperature with stirring and dry Nitrogen flow in 15 minutes 10 ml of a 70% NaAlH2 (0C2H40CH) 2 solution in benzene added. After refluxing for 24 hours, the reaction mixture becomes with ice-cooling with 5 ml of ethanol and then with 5 ml of ethanol / water mixture (1 + 1) decomposed.

The solvents are distilled off in vacuo, the residue in Suspended 20 ml of methanol and then precipitated in 100 ml of water, filtered off with suction, with water washed neutral and dried at room temperature. The dry residue will boiled with a methylene chloride / methanol mixture (261), filtered, on a rotary evaporator concentrated, crystallized, washed with hexane and dried at room temperature.

The following are obtained: 0.72 g of 1,3,5 (10), 6,8-strapentaen-3, 17β-diol vom Melting point 240-2420C from 2.00 g 1,3,5 (10), 7-stratetraen-3,17β-diol.

0.57 g of 1,3,5 (10), 6,8-oestrapentaen-3,17β-diol, melting point 239-242 ° C from 2.00 g 1,3,5 (10), 7-estratetraen-3-ol-17-one.

1.48 g of 3-methoxy-1,3,5 (10), 6,8-oestrapentaen-17β-ol, melting point 147-1480C from 2.00 g of 3-methoxy-1,3,5 (10), 7-oestratetraen-17β-ol.

1.05 g of 3-methoxy-1,3,5 (10), 6,8-oestrapentaen-17β-ol, melting point 147-149 ° C from 2.00 g of 3-methoxy-1,3,5 (10), 7-oestratetraen-17-one after 50 hours Heat.

1.04 g of 17,17-ethylenedioxy-1,3,5 (10), 6,8-oestrapentaen-3-ol of melting point 163-177 ° C from 2.00 g of 17,17-ethylenedioxy-1,3, -5 (10), 7-oestratetraen-3-ol.

I3 e i s p i e 1 2 1.00 g l7,17-ethylenedioxy-1,3,5 (10), 6,8-oestrapentaen-3-ol are dissolved in 15 ml of tetrahydrofuran and 10 ml of methanol.

With dilute hydrochloric acid (concentrated hydrochloric acid and water 2 + 1) is adjusted to pH = 1. Then 1 ml of water is added and taken for 2 hours Heated to reflux. It is concentrated in vacuo to a volume of 10 ml and cooled and precipitated in ice water, washed neutral and dried. After crystallization 0.78 g of equilenin with a melting point of 256-2580 ° C. are obtained from methanol with charcoal.

Claims (1)

Patent entitlement Process for the preparation of equilenin and equilenin derivatives of the general formula I. where R1 is a hydrogen atom or a methyl group and R2 is an oxygen atom, a β-hydroxy-α-hydrogen or protected oxygen group, characterized in that equilin or equilin derivatives of the general formula II in which R1 and R2 have the meaning given in formula I, reacts with sodium dihydrobis (2-methoxyethoxy) aluminate and, if appropriate, reoxidizes a 17-eetone which has been reduced in the reaction or splits off the protective group of a protected 17-ketone.