NO128976B - - Google Patents

Description

Process for the production of 6-methyl-3-oxo-4,6-diene steroids of the androstane and pregnane series.

The present invention relates to the production of new 6-methyl-3-oxo-4,6-diene steroids.

The invention provides new connections

of this type, which are of value because of their biological properties or as intermediate products in the production of other 6-methyl compounds with advantageous biological properties, such as e.g. 6-methyl-androstanolone.

The surprising fact has been found that the 6-methyl-6-dehydro-derivative of 3-oxo-A<4->steroid hormones can be more active with respect to hormonal action than the 3-oxo-4,6-diene derivatives of androstane and pregnane and even more active than the corresponding 3-oxo-A<4->steroid hormones.

Thus, one has e.g. found that the 6-methyl-6-dehydro derivative of ethisterone as a progestational agent is approximately twice as effective as ethisterone when given orally.

The 6-methyl-3-oxo-4,6-diene derivatives (I) of androstane and pregnane which are produced by the process according to the invention can be regarded as 6-dehydro derivatives of 3-oxo-6-methyl-A <4->steroids to which they can be transferred by hydrogenation. The 3-oxo-6-methyl-A<4->derivatives of androstane and pregnane are, as is known, of importance because of their biological properties.

With the help of the invention, 6-methyl-3-oxo-4,6-diene steroids of the androstane and pregnane series are obtained with the general formula:

where R, is an oxo group,

a p-hydroxy and an a-R, group, where R, is hydrogen, an alkyl,

alkenyl or alkynyl group with no more than 5 carbon atoms, or

a p-(CH-R,-CR,-)- and an a-R group where R,, and R, are hydrogen, acyloxy or alkyl groups with at most 5 carbon atoms, and R3 is oxo, (5-hydroxy or (3 -acyloxy.

In particular, the invention provides the new compounds: 6-methylandrosta-4,6-diene-3,17-dione, which is a dehydroderivative of 6-methyl-androstenedione, and is of value as an intermediate in e.g. the production of 6-methyl-dehydrotestosterone. 17p-hydroxy-6,17a-dimethylandrosta-4,6-dien-3-one which is the dehydroderivative of 6a,17ct-dimethyl-testosterone and has anabolic properties. 17p-hydroxy-17a-ethynyl-6-methylandrosta-4,6-dien-3-one which is the dehydro derivative of 6a-methyl-ethisterone and is an effective progestational agent when given orally.

6-methylpregna-4,6-dien-3,20-dione, which is the dehydroderivative of 6α-methylprogesterone, is a progestational agent and a valuable starting material in the production of the surprisingly effective 6-methyl derivatives of dehydrocortisone.

The invention provides a process for the production of 6-methyl-3-oxo-4,6-diene steroids of the androstane and pregnane series with the general formula (I). This method is characterized by reacting the corresponding 3(3-hydroxy or 3p-acyloxy-5a-hydroxy-6-oxo-steroid with the general formula:

where R is hydrogen or acyl with a methylmagnesium halide so that a 6-methyl-3p,5a,6-trihydroxy- is formed with the general formula: this steroid oxidizes to the corresponding 5a,6-dihydroxy-6-methyl-3 -oxo-steroid with the general formula:

and dehydrates the 5α,6-dihydroxy-6-methyl-3-oxo-steroid.

The 3p-acyloxy or 3|3-hydroxy-5a-hydroxy-6-oxo steroids which form the starting material in the above-mentioned process can be obtained in various ways, e.g. by oxidation of the corresponding 3|3-acyloxy-

5a,6p-dihydroxy steroids which can be produced from 3p-acyloxy-5,6-epoxy steroids by hydrolytic cleavage of the epoxy ring gene. Such reactions are well known and described in the literature.

When carrying out the method according to the invention, the 3p-acyloxy- or 3p-hydroxy-5a-hydroxy-6-oxosteroid (II) is transferred to the 6-methyl-3p,5a,6-trihydroxy-steroid (III), conveniently by -solution of the compound (II) (where R is hydrogen or an acyl group), where the solvent e.g. can be ether, butyl ether or a mixture of benzene and ether, is added to an excess of methylmagnesium halide. preferably the bromide or the iodide, and the reaction mixture is then boiled under reflux or allowed to stand at room temperature for several hours. The complex formed is then cleaved, and the steroid is extracted. The thus obtained 6-methyl-3p,5a,6-trihydroxy-steroid (III) can be mixed with its 3p-acyloxy derivative in amounts that depend on the reaction time used for the Grignard reaction and other conditions. It is therefore advisable to saponify the end product of the reaction in order to transfer the added 3p-acyloxy-5a,6-dihydroxy-6-methyl-steroid to the desired 6-methyl-3p,5a,6-trihydroxy-steroid (III).

The transfer of the 6-methyl-3p,5a,6-tri-hydroxy-steroid (III) to the corresponding 3-oxo-steroid (IV) can be carried out by oxidizing agents which are commonly used in the oxidation of secondary alcohols to the corresponding ketones. Chromium trioxide dissolved in acetic acid or in pyridine is thus well suited, however, when choosing an oxidizing agent, account must be taken of the nature of any additional substituents that may be present in the 6-methyl-3p,5a,6-trihydroxy steroid (III).

The dehydration of the 3-oxo-steroid (IV) and the desired 6-methyl-3-oxo-4,6-diene derivative (I) can be carried out by treating the compound (IV) in a solvent with a source of hydrogen ions , suitable hydrochloric acid. The reaction can be carried out e.g. by introducing hydrogen chloride into a solution of the 3-oxo-steroid (IV) at a temperature around 0° C. Alternatively, the dehydration can be carried out by dissolving the 3-oxo-steroid (IV) in a lower aliphatic alcohol with up to 5 carbon atoms, such as methanol or ethanol, with a little concentrated hydrochloric acid added, are heated under reflux.

The method according to the invention can be used for 3p-acyloxy or 3p-hydroxy-5a-hydroxy-6-oxo steroids of the androstane and pregnane type. Thus, the method can be used for the following compounds: 3|3-acyloxy-5ct-hydroxyandro-stan-6-one which at the C atom in the 17 position can have hydroxyl groups with or without alkyl, alkenyl or alkynyl groups which contain no more than 5 carbon atoms, as additional substituents, 3p-acyloxy-5a-hydroxypregnan-6-one, which at the C atom in the 20 position can be further substituted with an acyloxy or hydroxy group with or without acyloxy or alkyl -groups, which do not contain more than 5 carbon atoms at the C atom in the 17 or 21 position.

In the following, some embodiments of the method according to the invention are described as examples: Example 1: 17a-ethynyl-17$-hydroxy-methylandrosta-4, 6-dien-3-one (V).

3p-acetoxy-17a-ethynylandrostane-5a,

17p-diol-6-one (m.p. 245-247° C, [a] q = 103° in chloroform) (10.5 g) in a mixture of dry tetrahydrofuran (100 ml) and ether (100 ml) was added to a Grignard reagent prepared from magnesium (5.4 g), methyl iodide (15 ml) and ether (190 ml). The mixture was stirred for 2 hours at room temperature, after which it was allowed to stand for a further 18 hours. After treatment with dilute sulfuric acid, the organic layer was washed until it was neutral and then dried, and the solvents were removed. The residue was heated with methanolic potassium hydroxide (100 ml 2%'s) for 30 minutes under reflux. After addition of water, a product was obtained which crystallized from aqueous methanol in needles, 17a-ethynyl-6-methylandrostane-3p,5a,6-17p-tetrol, m.p. 254—255° C, [a] ^° 51° (c,

1.01 in ethanol).

This tetrol (4 g) in pyridine (40 ml) was added to a solution of chromium trioxide (4 g) in pyridine (40 ml) and the mixture was allowed to stand overnight. The product was extracted with ether and crystallized from aqueous ethanol, yielding needles of 17α-ethynyl-6-methylandrostane-5α,6,17β-triol-3-22

on, sm.p. 246—248° C, [a] D = 36° (c,

1.02 in ethanol).

This compound (1 g) in ethanol (25 ml) containing 2 drops of concentrated hydrochloric acid was heated for 30 minutes under reflux. The product was extracted with ether and crystallized from aqueous methanol, yielding needles of 17α-ethynyl-17β-hydroxy-6-methylandrosta-4,6-diene-3-20

on, sm.p. 200—201° C, [a] D = — 58°, (c,

1.03 in chloroform), XmaUs 290 m|x (log e = 4.36).

Example 2:

6- methylpregna- 4, 6- diene- 3, 20-dione (VI).

3β,20-diacetoxypregnan-5α-ol-6-one

20

(m.p. 224-225° C, [a] D = 48° in chloroform) (4.3 g) in benzene (200 ml) was added with stirring to a solution of methylmagnesium iodide which had been prepared from magnesium (4.3 g) and methyl iodide (12 ml) in dry ether (100 ml). The mixture was heated for 3 hours under reflux, cooled and treated with ice-cold ammonium chloride solution. The separated solid was crystallized from a mixture of acetone and hexane to give needles of 6-methylpregnan-3β,5α,6,20-tetrol, m.p. 220—

224° C, [a] D°= — 17° (c, 0.24 in chloroform).

This tetrol (1.5 g) in pyridine (15 ml) was added to chromium trioxide (3 g) in pyridine (30 ml) and the mixture was allowed to stand overnight. It was then filtered using an auxiliary filter, and the solid residue was washed with hot benzene (600 ml). The filtrate with the washing liquid was in turn washed with dilute hydrochloric acid, aqueous sodium carbonate and water, then dried and passed through a short column of aluminum oxide. Elution with ether gave 6-methylpregnan-5a, 6-diol-3,20-dione, which crystallized from a mixture of acetone and hexane in needles, m.p.

22

247—249° C [a] D = + 69° (c, 0.39 in chloroform).

This compound (300 mg) in methanol (50 ml) containing 2 drops of concentrated hydrochloric acid was heated for 30 minutes under reflux. The mixture was poured into a relatively large amount of water, and the solid separated substances were collected, washed and dried. Crystallization from hexane gave slabs of 6-methylpregna-4,6-diene-22 3,20-dione, m.p. 152-154° C, [a] D = +

176° (c, 0.56 in chloroform, Xm.lks 288.5 m^ (log = 4.37).

Example 3:

6, 17α-dimethyl-17α-hydroxyandrosta-4, 6-dien-3-one (VII).

3|3-acetoxy-5a,17|3-dihydroxy-17a-methylandrostan-6-one (m.p. 207-208° C,

24

[a] D - — 98° in chloroform) (6.5 g) in ether (300 ml) was added to a Grignard reagent prepared from magnesium (6.5 g) and methyl iodide (42 g) in a mixture of ether (300 ml) and benzene (200 ml). The mixture was heated for 3y2 hours under reflux, cooled and treated with an aqueous ammonium chloride solution. Separated solids were collected, washed and then saponified by heating with potassium carbonate (4 g) in methanol (180 ml) and water (20 ml) for one hour under reflux. The solvents were removed and the residue extracted with hot acetone. By adding hexane, needles of 6,17a-dimethylandrostane-3(3,5a,6,17p-tetrol,

20

sm.p. 233—234° C, [a] D = —24° (c, 0.55

in ethanol).

This tetrol (1.8 g) in pyridine (18 ml) was added to a solution of chromium trioxide (1.8 g) in pyridine (18 ml) and the mixture was allowed to stand overnight. The product was extracted with benzene and crystallized from a mixture of acetone and hexane, whereby

got needles of 6,17a-dimethylandrostane 5a,6,

23 17p-triol-3-one, m.p. 223—224° C, [a] D

= —25°, (c, 0.53 in chloroform):

This compound (1.85 g) in methanol (20 ml) containing concentrated hydrochloric acid (0.3 ml) was heated for one hour under reflux. The product was extracted with ether and recrystallized from a mixture of acetone and hexane to give 6,17α-dimethyl-17β-hydroxyandrosta-4,6-23dien-3-one, m.p. 157—158° C, [a] D = +38°

(c, 0.52 in chloroform) lnnU 290 m^i (log e= 4.37).

Example 4:

6- methylandrosta- 4, 6- diene- 3, 17-dione (VIII)

3β,17β-diacetoxy-5α-hydroxyandrostan-6-one (4 g) in benzene (250 mL) was added to a Grignard reagent prepared from magnesium (4 g) and methyl iodide (25 mL) in ether (50 mL ). The mixture was heated for 2 hours under reflux, cooled and treated with aqueous ammonium chloride. The separated solid was treated with potassium carbonate in water and methanol, whereby 6-methylandrostane-36.5a 617p-tetrol was obtained, which crystallized from acetone in the form of needles, m.p. 195—205° C (softens) [a] D 21

= 24° (c, 0.25 in ethanol).

This compound (3.3 g) in pyridine (33 ml) was added to a solution of chromium trioxide (6.6 g) in pyridine (66 ml) and the mixture was allowed to stand overnight. The product was extracted with benzene, purified chromatographically and crystallized from aqueous acetone. The obtained 5α,6-dihydroxy-6-methylandrostane-3,17-dione formed needles, m.p. 242—244° C,

21

[a] D = + 65° (c, 0.57 in chloroform).

This substance (0.5 g) in methanol (20 ml) containing 2 drops of concentrated hydrochloric acid was heated for one hour under reflux. The solid obtained after addition of water was washed, dried and crystallized from a mixture of acetone and hexane. 6-methylandrosta-4,6-diene-3,17-dione crystallized in needles, m.p. 164°C,

21

[a] D = + 139° (c, 0.51 in chloroform),

Xmax, 287 mji (log 6 = 4.37).

Claims (1)

Process for the preparation of 6-methyl-3-oxo-4,6-diene steroids of the androstane and pregnane series with the general formula: where Rj is an oxo group, a |5-hydroxy and an α-R2 group, where R2 is hydrogen, an alkyl, alkenyl or alkynyl group with no more than 5 carbon atoms, or a |3-(CH.2R4-CR5-)- and an a-R3 group where R3 and R4 are hydrogen, acyloxy or alkyl groups with no more than 5 carbon atoms, and R5 is oxo, |3-hydroxy or (3-acyloxy, which have anabolic, androgenic or progestational properties and/or are intermediates during manufacture of compounds with such properties, characterized in that the corresponding 3 (3-hydroxy- or 3 (3-acyloxy-5a-hydroxy-6-oxo-steroid with the general formula: where R is hydrogen or acyl, is reacted with a methylmagnesium halide so that a 6-methyl-3|3,5a,6-trihydroxy steroid with the general formula is formed: which is oxidized to the corresponding 5a,6-di-hydroxy-6-methyl-3-oxo-steroid with the general formula: which is then dehydrated.