NO132558B - - Google Patents

Description

Process for the preparation of 17a-hydroxy-6a-methyl-16-methylenepregn-4-ene-3,20-dione or its acyl derivatives.

The present invention relates to a

method for producing a new one

hydroxydione steroid, 17α-hydroxy-6α-methyl-16-methylenepregn-4-ene-3,20-dione with

the general formula:

(in which R is hydrogen), and its acyl esters. These new acyl esters, originally thought to be 17α-acyloxy-6α,16-dimethylpregn-4-ene-3,20-diones, are now believed to be acyl esters of the general formula

in which R is an acyl group containing

up to 10 carbon atoms. 3[3-hydroxy-6,16-dimethylpregna-5,16-dien-20-one is used as starting material in the production

with the general formula

The following new compound appears as an intermediate in the execution of the method: 6a,16-dimethyl-16a,17a-epoxypregn-4-ene-3,20-dione. The final product which is a new compound, which was first thought to be 17α-hydroxy-6α,16-dimethylpregn-4-ene-3,20-dione, but is now believed to be 17α-hydroxy-6α-methyl-16-methylenepregn- 4-ene-3,20-dione (I) when R = hydrogen finds application as a starting material especially for transfer to a compound originally thought to be 17α-acetoxy-6ct,16-dimethylpregn-4-ene-3,20 -dione, but which is now believed to have the structural formula II (when R is acetyl) which compound, together with the homologous esters, has value as a progestational agent.

Thus one finds e.g. by the known Clauberg's method for determining progestational effect that the acetoxydione II (when R is acetyl) is more than 100 times as powerful as dimethisterone (6a,21-dimethylethisterone; 6a,21-dimethylanhydrohydroxy-progesterone) when used orally. As dimethisterone is known to be somewhat more than 10 times as powerful as anhydrohydroxy-progesterone (ethisterone) by Clauberg's method and oral application, it will be clear to a person skilled in the art that said acetoxydione is a progestational agent of rather unusual action.

Other esters of formula II (in which R is an acyl group containing up to 10 carbon atoms) also exhibit progesterone-like or progestational properties. The new compounds of formula II (when R is acyl) are useful in the treatment of dysmenorrhoea, amenorrhoea, endometriosis and threatened abortion both in clinical and veterinary practice.

The above-mentioned new compounds of formula II can be prepared and used for the animal organism in a wide range of different dosage forms both orally and under the skin, individually or in admixture with other interacting compounds. The compounds can thus be used together with a pharmaceutical carrier which can be a solid or a liquid, in which the compound is dissolved, dispersed or suspended. The products used in solid form can be tablets, powders, capsules or pills, preferably in unit doses ready for use and/or to facilitate accurate dosing. The liquid products can be solutions, emulsions, suspensions, syrups or elixirs. The acetoxydione II (when R is acetyl) is the preferred acyl ester and is preferably used orally in the form of tablets.

According to the invention, 3|3-hydroxy-6,16-dimethylpregna-5,16-dien-20-one (III) is used as starting material, which compound can be prepared by condensation of 6-methylpregnadienolone with diazomethane, whereby the corresponding 3|3 -hydroxy-6-methyl-16,17 (2', 3' diazacyclopent-2'-en)pregn-5-en-20-one, which on pyrolysis is easily transferred to the above-mentioned 6,16-dimethyl-pregnadienolone (III) .

The invention provides a process for the preparation of 17a-hydroxy-6a-methyl-16-methylenepregn-4-ene-3,20-dione (I; when R is hydrogen) or its acyl derivatives, and the main characteristic feature of the invention is that 3( 3-hydroxy-6,16-dimethylpregna-5,16-dien-20-one is oxidized by Oppenauer's method to form 6a, 16-dimethylpregna-4,16-dien-3,20-dione with the general formula

which is reacted with alkaline hydrogen peroxide so that a 16a,17a-epoxide with the general formula is formed

which is treated with a hydrogen halide, after which the product obtained is subjected to reaction with Rahney nickel in an organic solvent, after which the 17a-hydroxyl group is optionally acylated.

6a,16-dimethylpregna-4,16-diene-3,20-dione is transferred to the corresponding 16a,17a-epoxide by reacting it with alkaline hydrogen peroxide in a water-miscible organic solvent, such as e.g. methanol or ethanol, at temperatures between 0° and 100° C and preferably at the reflux temperature of the reaction mixture. The epoxy derivative thus obtained is then treated with a hydrogen halide. This reaction is preferably carried out with hydrogen bromide in an aliphatic acid, for example acetic acid, mixed with an inert organic solvent such as benzene or dioxane, at a temperature that is preferably in the range 0°-10° C. Alternatively, aqueous hydrogen iodide can be used in a water-miscible organic solvent, such as e.g. dioxane or tetrahydrofuran, at temperatures in the range 0°—10°C.

The product thus obtained is treated with Rahney nickel in an organic solvent, such as e.g. ethanol or acetone, at room temperature to form 17α-hydroxy-6α-methyl-16-methylenepregn-4-ene-3,20-dione (I; when R is hydrogen).

The acetylation of the above-mentioned 17α-hydroxy compound to form the acetyl compound (II, when R is acetyl) is carried out in a manner known per se. Thus, the acetylation can e.g. is carried out using an acetylation mixture comprising glacial acetic acid, acetic anhydride and a catalytic amount of toluene-p-sulfonic acid monohydrate at room temperature or using a mixture comprising acetic anhydride and a catalytic amount of toluene-p-sulfonic acid monohydrate.

It is unequivocally established according to the time-

other literature that 16a,17a-epoxypregnan-20-ones (VI) react with hydrogen halides to form 17a-hydroxy-16|3-halopregnan-20-ones (VII), which derivatives upon treatment with a catalytic reducing agent gives the corresponding 17α-hydroxypregnan-20-ones (VIII).

It was therefore concluded that extending this method to the 16-methyl derivative (V) in an analogous manner would give the corresponding 17α-hydroxy-6α,16-dimethylpregn-4-ene-3,20-dione ( where R is hydrogen), which when forced acylation would give the corresponding 17α-acyloxy-16-methyl derivative (IX; when R is an acyl group). The ultraviolet and infrared absorption spectra of the acylated product also proved in reality to be fully consistent with this:

It was therefore concluded that the reactions proceeded as expected according to what was previously known and the formulas for the products were set up accordingly.

Subsequently, however, the reaction between the epoxide (V) and sulfuric acid in dioxane was investigated, by which it was hoped to produce the corresponding 16-methyl-16,17-diol (X).

Surprisingly, the product turned out to be identical to the new compound originally attributed to the formula 17α-hydroxy-6α,16-dimethylpregn-4-ene-3,20-dione (IX; when R is hydrogen) and which was obtained from the epoxide (V) by successive treatment with hydrogen halide and Rahney nickel. This remarkable finding, which as far as is known has no exact counterpart in the literature, was clearly incompatible with the formula 17a-hydroxy-6a,16-dimethylpregn-4-ene-3,20-dione, but pointed in the direction of the alternative formula 17a -hydroxy-6a-methyl-16-methylenepregn-4-ene-3,20-dione (I; when R is hydrogen, cf. XI) or isomers thereof (XII). Formula XI is preferred due to theoretical considerations. A formula corresponding to a conventional D-homostructure formed from either X, XI or XII by molecular rearrangement is considered unlikely, as reduction of the carbonyl group on ring D, followed by oxidation of the resulting glycol with periodate, leads to an α(3-unsaturated ketone which is assumed to have partial structure (Xlla or XHIb).

Forced acetylation of the new compound, which is now believed to be 17α-hydroxy-6α-methyl-16-methylene-pregn-4-ene-3,20-dione (I; where R is hydrogen, cf. XI), gives an acetyl derivative which is a powerful orally active progestational substance. The acetyl derivative's formula 17a-acetoxy-6a,16-dimethylpregn-4-ene-3,20-dione (IX; where R is acetyl) must now obviously be revised in light of the new formula I, where R is hydrogen, for the substance's hydroxy learned precursor. From the material currently available, however, one cannot allow oneself to draw the conclusion that acylation of the compound I (where R is hydrogen) necessarily takes place during the formation of the compound I (where R is an acyl group), without accompanying molecular rearrangement . The justification for this doubt will be found below.

Examination of the acetylated substance using methods that are based on magnetic resonance in the nucleus shows, among other things, a. an absorption of 4.6 parts/million relative to tetramethylsilane (used as an internal standard) in the olefinic proton region, which absorption is believed to indicate (i) the presence in the acylated material of three ordinary inactivated protons, preferably bound to cyclohexane rings, and (ii) absence of the methylene (> C = CH.2), which normally shows absorption at 5.2-5.4" parts/million relative to tetramethylsilane as an internal standard. In addition, the absorption spectrum appears based on magnetic resonance to show the presence of only one methyl group (at carbon atom no. 6) in the molecule (other than the angular methyl groups at carbon atoms no. 10 and 13). These observations can hardly be reconciled with the structure I, where R is acetyl, for the acetyl derivative. Rik- the science dealing with nuclear magnetic resonance is still in its infancy so that conclusions drawn on the basis of it must not be accepted without further ado. sonance in the core, does not allow the easy conclusion that the acyl derivatives which make up the final products according to the invention are precisely acyl derivatives of formula I (when R is acyl) of the hydroxylated precursor (I; when R is hydrogen). Formula II (when R is acyl) is therefore the preferred formula for these valuable new compounds.

In the following, some examples will be given of the implementation of the method according to the invention.

Example 1:

(a) 6a,16-dimethylpregna-4,16-diene-3,20-dione. 1 g of 3(3-hydroxy-6,16-dimethylpregna-5, 16-dien-20-one was dissolved in 24 ml of cyclohexanone, and the solution was slowly distilled until 6 ml of distillate was collected. There was added 1 g of aluminium- tert-butoxide in 16 mL of dry toluene, and the reaction mixture was heated for 45 minutes under reflux. Rochelle salt solution was then added, and the mixture was evaporated-stilled for 4 hours. The steroid was extracted with ether, and the ether extracts were washed with water and dried. After the ether was removed, the residue was recrystallized from methanol, whereby 6α,16-dimethylpregna-4,16-diene-3,20-dione was obtained in the form of T^tOH laughs, sm.p. 188-190°C, X = 242-244

chloroform).

(b) 6a,16-dimethyl-16a,17a-epoxypregn-4-ene-3,20-dione. 5 g of 6α,16-dimethylpregna-4,16-diene-3,20-dione was dissolved in 50 ml of ethanol containing 2.5 ml of 40% sodium hydroxide, and 10 ml of 30% hydrogen peroxide was added dropwise as the mixture was heated to boiling under reflux. Reflux was continued for a further 20 minutes, after which the solution was cooled. The crystallized product was filtered off and recrystallized from methanol, whereby 6α,16-dimethyl-16α,17α-epoxypregn-4-ene-3,20-dione was obtained in needles, m.p. 175—177° C. (c) 17a-hydroxy-6a-methyl-16-methylene-pregn-4-ene-3,20-dione (I; R = H).

4 g of the above 16a,17a-epoxide was dissolved in 250 ml of glacial acetic acid and 100 ml of benzene and treated with hydrogen bromide in 6 ml of 50% acetic acid at 0° C. The mixture was

stirred for 30 minutes and then poured into water, and the product was isolated with chloroform. After evaporation of the extracts, the residue was dissolved in 250 ml of acetone and re-

stirred for 4 hours with 10 g of Rahney nickel at room temperature. The Rahney nickel was filtered off and the acetone evaporated under reduced pressure. The residue was recrystallized from acetone/hexane, whereby 17α-hydroxy-6α-methyl-16-methylenepregn-4-ene-3,20-dione was obtained in needles,

sm.p. 210—212° C, [a] D : — 15° (c = 0.598

EtOH in chloroform), l max. = 239.5 m^, e =

17,638; y max3: 1608, 1661' 1689' 1708,

3485, 3605 cm-<1>. (d) The acetyl derivative of 17<x- hydroxy- 6a-methyl- 16- methylenepregn- 4-ene- 3, 20-dione (II; R = acetyl).

1 g of 17α-hydroxy-6α-methyl-16-methylene-pregn-4-ene-3,20-dione (I) and 500 g of p-toluenesulfonic acid monohydrate were dissolved in 40 ml of glacial acetic acid and 8 ml of acetic anhydride, and the mixture obtained stand for 8 hours at room temperature. Water was added to the reaction mixture and after standing overnight the product was extracted with ether. The ether extracts were washed with water, sodium bicarbonate solution, water, dried and evaporated under reduced pressure. The residue was recrystallized from acetone/hexane, whereby the above-mentioned acetyl derivative was obtained with the following ca-EtOH characterizing physical data: }. max

CHC1 = 239 m|x, log 6 = 4.19; y max'J: 1738,

1715, 1666 and 1615 cm-<1>.

Example 2: The acetyl derivative from 17a-hydroxy-6a-methyl-16-methylenepregn-4-ene-3,20-dione

(II; R = acetyl)

1 g of 17α-hydroxy-6α-methyl-16-methylene-pregn-4-ene-3,20-dione (I) and 300 mg of p-toluenesulfonic acid monohydrate were stirred in 20 ml of acetic anhydride for 18 hours at room temperature. The suspension was poured into water, whereby excess anhydride was hydrolysed. The precipitated substance was filtered off, washed and dried. It was dissolved in 100 ml of methanol and treated with 0.9 g of potassium hy-

droxyd dissolved in 4 ml of water and 10 ml of methanol for 7 hours at room temperature. 2 ml of acetic acid was added; and the solution was evaporated under reduced pressure to a small volume. Water was added there, and the precipitated substance was collected and dried. The product was purified by chromatography on aluminum oxide followed by elution with benzene, whereby the above-mentioned acetyl derivative was isolated. Recrystallization from aqueous methanol gave needle-shaped crystals, m.p. 203—207°C,

22 [a] D : —99° (c = 0.214 in chloroform), l EtOH max.= 240 m^ (log e 4.19)-Example 3: The caproyl derivative from 17a- hydroxy- 6a- methyl- 16- methylenepregn- 4- en- 3, 20-dione

(II; R = CO.C5Hn).

1.0 g of 17α-hydroxy-6α-methyl-16-methylenepregn-4-ene-3,20-dione was treated with 22 ml of n-caproic anhydride and 0.5 g of toluene-p-sulfonic acid monohydrate for 20 hours at 45° C. Aqueous pyridine was added there, and the mixture was steam distilled for 1 hour and the product isolated with ether, whereby the above-mentioned caproyl derivative was obtained as a low-melting solid, characterized by EtOH max. = 239 l0S e = 4'2-

Claims (1)

Process for the production of therapeutically active 17a-hydroxy-6a-methyl-16-methylenepregn-4-ene-3,20-dione or its acyl derivatives, characterized in that 3(3-hydroxy-6,16-dimethylpregna-5, 16-dien-20-one is oxidized by Oppenauer's method to form 6a,16-dimethylpregna-4,16-dien-3,20-dione, which is then reacted with alkaline hydrogen peroxide to form a 16a,17a-epoxide, which is treated with a hydrogen halide followed by treatment with Rahney nickel in an organic solvent, after which the 17a-hydroxyl group is optionally acylated.