NO118317B - - Google Patents

Description

Process for the preparation of 17"-alkyl derivatives of 19-nortestosterone.

The present invention relates to the production of a previously unknown group of

blood pressure-lowering and anabolic agents

with little androgenic activity, namely 19-nortestosterone derivatives, which are substituted in the 17a position with a lower alkyl radical, containing 2-8 carbon atoms.

The compounds referred to here can

is reproduced by the general structural formula

where R is a lower alkyl group with 2-8

carbon atoms, e.g. an ethyl group or

a straight or branched propyl, butyl, pentyl, hexyl, heptyl or octyl group.

The compounds in question here are

valuable anabolic agents, i.e. they promote nitrogen retention. They have this one

effect at a dosage that only results in a very small degree of androgenic activity. It is well known that testosterone propionate is an effective anabolic agent, but

this compound's clinical utility to this

purpose is severely limited, because the androgenic effects are undesirable in many patients. When using the compounds referred to here, the effective anabolic doses are so small that long-term administration

have practically no unwanted side effects.

Another important area of application for

these compounds are due to their action

against high blood pressure, which does not exist

in 19-nortestosterone or its 17-methyl derivative. The compounds referred to here are particularly effective in overcoming the increase in blood pressure caused by the adrenal cortical hormone desoxycorticosterone.

According to the invention, the compounds in question are prepared by isomerizing a 3-oxo-17a-alkyl-5(10)-estren-17-ol, in which the alkyl group has 2-8 carbon atoms, to a 17-alkyl-19-nortestosterone. The isomerization can be brought about under the influence of a basic agent, e.g. sodium hydroxide in aqueous methanol, or an acidic agent, such as hydrochloric acid or p-toluenesulfonic acid in aqueous methanol, whereby the double bond migrates from the 5-10 position to the 4-5 position, whereby a compound of the desired configuration.

A 3-oxo-17a-alkyl-5(10)-estren-17-ol is conveniently prepared by a series of reactions, which comprise ethynylation with acetylene of a lower alkyl ether of estrone. catalytic hydrogenation of the 17-ethynyl group to a 17-ethyl group and a Birch-type reduction of the formed 17α-alkyl-estradiol-3-monoalkyl ether with lithium and ammonia, followed by mild acid hydrolysis. In an appropriate modification of this method, the product obtained by the Birch reduction: a 17a-alkyl-3-alkoxy-2,5(10)-est-radien-17-ol, is subjected to a stronger acid hydrolysis, whereby the enol ether residue in the 3-position is cleaved, the formed 3-enol compound is ketonized, and the 5-10 double bond is moved to a conjugated position in relation to the 3-ketone group in one operation in the same reaction vessel, without it being necessary to isolate the 3-oxo-17a-alkyl-5 (10)-estren-17-ol formed as an intermediate product. It will be clear that the direct conversion of 17cc-alkyl-3-alkoxy-2,5(10)-estradien-17-ol to a 17-alkyl-19-nortestosterone must proceed through the isomerization of a 3-oxo-17a- alkyl-5(10)-estren-17-ol to a 17-alkyl-19-nortestosterone. In the direct conversion of the homoannular unconjugated diene-17α-alkyl-3-alkoxy-2,5(10)-estradien-17-ol, 3-oxo-17c-alkyl-5(10)-estrene-17- ol in the reaction mixture as an unisolated intermediate which is isomerized to 17-alkyl-19-nortestosterone. Similarly, the 3-oxo-17a-alkyl-5(10)-estren-17-ol can be present as an unisolated intermediate by conversion of a 17n-alkyl-3-alkyl-1,3,5(10)-estratriene- 17-ol

to a 17-alkyl-19-nortestosterone.

Compounds of the kind referred to here with particularly good activity as mentioned above, and which can be produced by the method according to the invention, are those in which the alkyl group is an ethyl group. Compounds in which the alkyl group is a propyl group are also particularly suitable.

According to the invention, the isomerization is carried out preferably with the aid of a mineral acid.

In a particularly suitable embodiment of the method according to the invention, the starting point is 17a-ethyl-3-methoxy-2,5(10)-est-radien-17-ol, and 3-oxo-17a-ethyl-5(10)- estren-17-ol is then present as an unisolated intermediate product which is isomerised to 17-ethyl-19-nortestosterone when treated with mineral acid.

The method according to the invention will be explained in more detail in the examples below. In these examples, parts means parts by weight.

Example 1.

5 parts of allyl bromide in 15 parts of ether are added to a stirred mixture of 8.5 parts of magnesium in 140 parts of ether. In the course of 45 minutes, a mixture of 20 parts of the methyl ether of estrone and 95 parts of allyl bromide in 630 parts of ether is then added. After boiling for 3 hours under reflux, the mixture is cooled to 0° C., after which it is repeatedly washed with 10% ammonium chloride solution and then with water, dried over anhydrous sodium sulfate, filtered and evaporated. The rest is taken up in ether. The ether solution is partially concentrated and diluted with petroleum ether. The crystalline 17α-allyl-3-methoxy-1,3,5(10)-estratrien-17-ol thus formed melts at approx. 91-91.5° C.

A mixture of 11.5 parts 17'-allyl-3-methoxy-1,3,5(10)-estratrien-17-ol, 3 parts

charcoal, which contains 5 per cent palladium, and 160 parts of ethanol are hydrated until one mole of water has been absorbed. Next, the mixture is filtered using a filter aid, and the filtrate is evaporated under vacuum. The residue is recrystallized from a mixture of ether and methanol, whereby 17α-propyl-3-methoxy-1,3,5(10)-estratrien-17-ol is obtained, which melts at approx. 93— 94° C.

To a stirred mixture of 6 parts of 17a-propyl-3-methoxy-1,3,5(10)-estratrien-17-ol in 500 parts of ammonia and 140 parts of ether, 7 parts of lithium are added over the course of 20 minutes. The mixture is stirred for 30 minutes, after which 46 parts of ethanol are added dropwise over the course of an hour. The stirring is continued until all the ammonia has disappeared. Water is then added, and the ether layer is separated, washed with water, dried over anhydrous sodium sulphate, filtered and evaporated. The crystallization from a mixture of ether in methanol gives 17α-propyl-3-methoxy-sy-2,5(10)-estradien-17-ol, which melts at approx. 150—152° C.

A mixture of 18 parts of 17α-propyl-3-methoxy-2,5(10)-estradien-17-ol, 320 parts of methanol, 80 parts of water and 18 parts of concentrated hydrochloric acid is boiled under reflux for 5 minutes, after which it is allowed to stand 15 minutes in warm water. So much hot water is added that the mixture becomes cloudy. On standing, 17-propyl-19-nortestosterone precipitates, which after crystallization from a mixture of acetone and petroleum ether melts at 120-122°C.

Example 2.

To a stirred suspension of 16.5 parts of the methyl ether of estrone in 300 parts of ether is added a solution of butyllithium prepared from 115 parts of 1-bromobutane and 6.7 parts of lithium in 600 parts of ether. Stirring is continued for one hour, after which the mixture is split with methanol and dilute sulfuric acid and extracted with ether. The resulting extract is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under nitrogen. The residue is crystallized from methanol and water and then placed in benzene solution on a chromatography column containing 1000 parts of alumina. The column is washed with 1800 parts of a 10% solution of petroleum ether in benzene and then eluted with 9000 parts of a 10% solution of petroleum ether in benzene. The resulting eluate is evaporated, and the residue is recrystallized from aqueous methanol, whereby 3-methoxy-17a-butyl-1,3,5(10)-estratriene-17(3-ol is obtained.

To a solution of 37.2 parts of this compound in 500 parts of ether and 500 parts of liquid ammonia, 3.5 parts of short pieces of lithium wire are added while stirring. The dark blue solution is stirred for 10 minutes, after which 32 parts of methanol are added dropwise over the course of 15 minutes to decolorize the solution. Next, a further 56 parts of methanol are slowly added, and when most of the ammonia has evaporated, 1100 parts of ether and 700 parts of water are added with stirring. The organic layer is separated, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under vacuum. 1110 parts of methanol and 500 parts of water are added to the oily residue, after which the mixture is heated to boiling under reflux cooling. Next, 240 parts of concentrated hydrochloric acid are added, and the boiling under reflux cooling is continued for 6 minutes. The mixture is then extracted with ether. The ether solution is washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated under vacuum. The residue is placed in benzene on a chromatographic column containing 350 parts of silica gel. The column is washed with 500 parts of benzene and then with 3000 parts of a 10% solution of ethyl acetate in benzene. Elution with 2000 parts of a 20% solution of ethyl acetate in benzene, concentration of the eluate and crystallization from aqueous methanol gives 17-butyl-19-nortestosterone, which melts at approx. 127-128° C.

Example 3.

When an equivalent amount of 1-bromooctane is used instead of 1-bromobutane in the method described in the previous example, 17-octyl-19-nortestosterone is obtained. The infrared absorption spectrum of this compound shows maxima at 2.8 and 6.05 µm. The ultraviolet absorption spectrum shows a maximum at 240.5 mii with a molecular extinction coefficient of 17,000.

Example 4.

A mixture of 10 parts of 17"-ethynyl-3-methoxy-1,3,5(10)-estratrien-17-ol, 2.5 parts of a catalyst, consisting of charcoal with 5% palladium, and 50 parts of dioxane shaken in contact with a hydrogen atmosphere, until 2 mole equivalents of hydrogen have been used. The catalyst is removed by filtration, and the residue remaining after the concentration of the filtrate is purified by recrystallization from a mixture of ether and petroleum ether. In this way, 17α-ethyl-3-methoxy-1,3,5(10)-estratrien-17-ol is obtained which melts at approx. 88-89° C.

A solution of 50 parts of 17"-ethyl-3-methoxy-1,3,5(10)-estratrien-17-ol in 710 parts of ether is diluted with 2500 parts of liquid ammonia. In the following operations, until the reaction mixture is diluted with water, it is constantly stirred, and it is kept at an approximately constant volume by the addition of a total of 2100 parts of ether in portions to replace the ammonia which is continuously lost by evaporation.

The solution of 17α-ethyl-3-methoxy-1,3,5(10)-estratrien-17-ol in ether and liquid ammonia is treated over a period of 35 minutes by adding a total of 35 parts of lithium in small portions.

After another hour, 240 parts of ethanol are added in small portions over the course of 3 hours, and stirring is continued for several hours. 1000 parts of water are added, and the ethereal phase is washed with several portions of water, after which it is dried and concentrated. The residue obtained by mixing the ethereal solution is stirred with a mixture of 200 parts methanol and 1 part pyridine, and the resulting suspension is cooled for several hours. The crystalline product is collected on a filter and washed with 120 parts of cold methanol. The resulting compound is 17α-ethyl-3-methoxy-2,5(10)-estradien-17-ol, which melts at approx. 127-128° C.

A mixture of 1.25 parts of 17α-ethyl-3-methoxy-2,5(10)-estradien-17-ol, 24 parts of methanol and 4 parts of acetic acid is heated under reflux for 5 minutes. 150 parts of water are added, and the mixture is cooled down for several hours. The precipitated product is collected on a filter and dried. By recrystallization from a mixture of acetone and petroleum ether, 17a-ethyl-3-oxo-5(10)-estren-17-ol is obtained, which melts at approx. 134— 136° C.

A mixture of 10 parts of 17α-ethyl-3-oxo-5(10)-estren-17-ol, 160 parts of methanol, 20 parts of water and 7 parts of concentrated hydrochloric acid is stirred for 2 hours at room temperature, after which it is cooled and allowed to stand at 0 ° C for 2 hours. The mixture is filtered through a small amount of insoluble material, and the filtrate is diluted under constant stirring with 500 parts of water. The mixture is then cooled to approx. 0—5° C, after which it is filtered. The crystalline product can be purified by recrystallization from aqueous methanol or from a mixture of acetone and petroleum ether. In this way, 17-ethyl-19-nortestosterone is obtained, which melts at approx. 140-141° C.

Example 5.

A mixture of 36 parts of 17α-ethyl-3-methoxy-2,5(10)-estradien-17-ol, 475 parts of methanol, 70 parts of water and 25 parts of concentrated hydrochloric acid is stirred for 2 hours at room temperature, after which it is allowed to stand at 0— 10° C for approx. 2 hours. The mixture is filtered from a small amount of insoluble material, and the filtrate is diluted with constant stirring with 2000 parts of water. The mixture is then cooled to approx. 0-5° C, and the crystalline product is collected on a filter. Recrystallization from aqueous methanol or from a mixture of acetone and petroleum ether gives pure 17-ethyl-19-nortestosterone, which melts at approx. 140-141° C.

Similarly, 17α-ethyl-3-ethoxy-2,5(10)-estradien-17-ol (prepared by ethynylation of estrone ethyl ether followed by hydrogenation of the ethynyl group and reduction of the product formed with lithium and ommo- niakk) 17-ethyl-19-nortestosterone by treatment with mineral acid as described above.

Example 6.

7.8 parts of potassium, washed with toluene, tertiary amyl alcohol and ether, are added to 125 parts of tertiary amyl alcohol, and the stirred reaction mixture is heated under reflux in a nitrogen atmosphere for 2 hours. It is then cooled to approx. 0° C and a solution of 24 parts of 1-octyne in 90 parts of ether is added. After stirring the mixture for a further 1 hour, a suspension of 5.7 parts of estrone methyl ether in ether is quickly added. The reaction mixture is stirred in a nitrogen atmosphere at approx. 0° C. for a further 5 hours, after which it is allowed to assume room temperature, and it is further stirred for 16 hours. It is cooled again to 0° C, and the product is mixed well with a solution of 15 parts ammonium chloride in 150 parts water. The ethereal phase is separated, washed with several portions of ammonium chloride solution and with water, dried and concentrated to a brown residual oil. A mixture of 4 parts of this crude product which is predominantly 17"-octynyl-3-methoxy-1,3,5(10)-estratrien-17-ol, 1 part 5% palladium on charcoal as catalyst and 75 parts dioxane, is shaken in contact with a hydrogen atmosphere, until the water-substance absorption, which is initially very rapid, has become very slow. At this point, up to approximately 2 mole equivalents of water will have been consumed. The catalyst is removed by filtration,

and the residue that remains after concentration of the filtrate is purified by chromatographic fractionation on a silica gel column or by recrystallization from methanol. In this way, 17a-octyl-3-methoxy-syl-1,3,5(10)-estratrien-17-ol is obtained, which melts at approx. 80-81° C.

A solution of 2.5 parts of 17α-octyl-3-methoxy-1,3,5(10)-estratrien-17-ol in 70 parts of ether is diluted with 205 parts of liquid ammonia. This stirred solution is treated over a period of 30 minutes by adding a total of 2.5 parts of lithium in small portions. After a further 1 hour, 20 parts of ethanol are added in small portions over the course of 3 hours, and the stirring is continued for several hours. During the preceding operations, a further 70 parts of ether have gradually been added to replace some of the ammonia, which has been lost by evaporation. 80 parts of water are added, and the ethereal phase is washed with several portions of water, after which it is dried and concentrated. The residue resulting from evaporation of the ethereal solution is washed with a small volume of cold methanol, which contains approx. 1 percent pyridine, after which it is purified by recrystallization from a mixture of ether and methanol. In this way, 17a-octyl-3-me-thoxy-2,5(10)-estradien-17-ol is obtained, which melts at approx. 50—55° C. A mixture of 1.1 part of this compound, 24 parts of methanol, 6 parts of water and 1.2 parts of concentrated hydrochloric acid is heated under reflux for 10 minutes, cooled and diluted with several times its volume of water. Purification of the precipitated product by crystallization from aqueous methanol yields 17-octyl-19-nortestosterone, which melts at approx. 120— 122° C.

Claims (3)

1. Process for the production of 17a-alkyl derivatives of 19-nortestosterone with blood pressure-lowering and anabolic effects and with little androgenic activity, characterized in that a 3-oxo-17a-alkyl-5(10)-estren-17-ol, in which the alkyl group has 2-8 carbon atoms, is isomerized to a 17a-alkyl-19-nortestosterone, preferably with the help of a mineral acid. 2. Process according to claim characterized in that the alkyl group is an ethyl group. 3. Process according to claim 1, characterized in that the alkyl group is a propyl group.