NO134553B - - Google Patents

Description

The present invention" relates to a new method

for the production of steroid compounds and more particularly in the process for the production of steroidal 17a-allenes.

Some of these steroid compounds with a 17a-

ethylenically unsaturated side chain, especially a 17a_propadienyl(allene) group are new, especially 17a-propadienyl steroids of the 6,6-difluoroandrostane and -19-norandrostane series and the 17a-propadienyl-

steroids of the ' ^ ^10 ^' 1"'"-androstarien series indicated respectively by formulas (A) and (B).

Other 17α-propadienyl steroids have previously been described. Thus describes e.g. U.S. patents 3-392,165 and 3,392,166 derivatives of estrogen, estr-4-ene, estr-5(10)-ene and anrost-4-ene series as indicated by the formulas (II), (III) and

(IV).

In these and the following formulas R is hydrogen or lower alkyl with 1-3 carbon atoms, R <2> is hydrogen, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl or a carboxylic acyl group with up to 12 carbon atoms, R" is an oxo group or the group R 0 :_, where R is hydrogen, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, 4-methoxytetrahydro-pyran-4-yl or a carboxylic acyl group with up to 12 carbon atoms, R 11 is hydrogen or methyl and ~ RJ c is hydrogen, lower alkyl of 1-8 carbon atoms, cycloalkyl, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, or a carboxylic acyl group with up to 12 carbon atoms.

The 17a-propadienyl derivatives in the estra-1,3,5(10)-triene series (formula II) have estrogenic and antiandrogenic activity and can be used in the way such agents are usually used for the treatment of conditions that can be influenced by estrogens and antiandrogens remedies, such as regulation and control of fertility and treatment of acne, benign prostatic hypertrophy and hirsutism in women. The 17α-propadienyl derivatives of the 6,6-difluoroandrostane, 6,6-difluoro-19-norandrostane, estr-5(10)-ene, estr-4-ene and androst-4-ene series (formula A, III and IV) has progestative and mucus-secreting inhibitory activity, and can therefore be used for the treatment of various menstrual disorders and for the regulation and control of fertility.

The 17a-propadienyl compounds in the >9(lo)»H_anciro-statrien series (formula B) have progestative and antifertility activity and can be used in a manner corresponding to such activity, e.g. as described above.

The present invention is particularly applicable for the production of 17a-propadienyl steroids in the estrogen, estran and androstane series, as stated above in the formulas (A),

(B), (II), (III) and (IV).

According to the present invention, the above-mentioned I<7>a-propadienyl steroids are produced by a 17a-(3-substituted propynyl)-steroid, where the substituent is tetrahydrofuran-2-yl-oxy, tetrahydropyran-2-yl-oxy, 4-methoxytetrahydropyran -^-yloxy, halogen, alkylsulfonyloxy or arylsulfonyloxy,

is treated with an aluminum hydride reagent, suitably in an organic liquid reaction medium and at a temperature of about cU-120°C.

Suitable aluminum hydride compounds include those containing at least two available hydrogen atoms, e.g. aluminum hydride, lithium aluminum hydride, lithium di-(2-methoxyethoxy) aluminum hydride, lithium diisobutylaluminum hydride and sodium aluminum hydride, lithium aluminum hydride being preferred.

The aluminum hydride compound is suitably used in amounts that at least chemically equivalently correspond to the amount of the steroid used. One can appropriately use surplus in relation to this, e.g. an excess of 20-50 mol. Preferred embodiments include using from 1.5 - 20 mol of said aluminum hydride compound per moles of the starting steroid.

Suitable reaction media include common organic solvents, e.g. ethers, such as dimethyl ether, dioxane, methyl propyl ether and tetrahydrofuran; saturated aliphatic hydrocarbons, such as pentane, hexane and octane; besides aromatic hydrocarbons such as benzene, toluene and mesitylene.

The reaction is preferably carried out at the boiling point of the reaction mixture and under reflux conditions. The reaction is carried out for a sufficiently long period of time for the reaction to be complete, i.e. from approx. 2 to approx. 45 hours. Longer or shorter periods can be used, all depending on the choice of reaction temperature and reactants.

In a preferred method, the starting steroid compound is dispersed in an organic liquid reaction medium, treated with the aluminum hydride compound on the basis of at least 1 mole per mol. The resulting reaction mixture is then heated with stirring for shorter or longer periods of time. When the reaction is complete, the product is separated and recovered from the reaction mixture in a known manner. Such known ways are e.g. filtration, decantation, evaporation, chromatography, recrystallization and the like.

The starting compounds, namely tetrahydrofuran-2-yloxy, tetrahydropyran-2-yloxy and 4-methoxytetrahydropyran-M-yloxy ethers of the 17α-(3-hydroxypropynyl) steroid compounds can be prepared by treating the corresponding 17-oxosteroid with a Grignard reagent prepared by treat the reaction product of propargyl alcohol and dihydrofuran, dihydropyran and 4-methoxy-5, 6-dihydro-2H-pyran (3-tetra-hydrofuran-2'-yloxy-propyne, 3-tetra-hydropyran-2'-yloxypropyne and 3-( 4'-methoxytetrahydropyran-4'-yl-(oxy)propyne, respectively) with ethylmagnesium bromide in a manner known per se. In this way, the corresponding 17a-(3-tetrahydrofuran-2'-yloxypropynyl), 17a-(3_'tetrahydropyran-2'-yloxypropynyl), and 17a-(3~(4'-methoxytetrahydropyran-4'-yloxy )-propynyl)-steroid starting compounds.

Parent steroid compounds containing a 17α-(3-halopropynyl) group can be prepared from the corresponding 17α-(3-hydroxypropynyl) compounds which can be prepared from the corresponding ethers (prepared as described above) by conventional hydrolysis, e.g. with a mineral acid or an organic acid. This halogenation-displacement conversion is carried out in the bromine and chlorine series by treating the hydroxy compound with thionyl bromide or phosphine pentabromide or with thionyl chloride or phosphorus pentachloride in the presence of a tertiary amine base, such as tertiary alkylamines, pyridine and lutidine. The reaction is carried out in a known manner and at temperatures from 0 - 20°C, suitably in an organic liquid reaction medium, e.g. ether and benzene.

In the fluoro series, the hydroxy compound is treated with a hydrocarbon sulfonyl fluoride, including benzylsulfonyl fluoride, tosyl fluoride, and mesyl fluoride. This method also preferably uses an inert hydrocarbon solvent such as hexane, heptane, benzene, toluene or an esterified or denatured alcohol, e.g. dimethoxyglycol. Other suitable solvents are chloroform and nitromethane. The reaction is carried out at temperatures from 0 to 150°C for a period of 1-8 hours.

The 17ct-(3-arylsulfonyloxypropynyl) and 17a-(3-alkyl-sulfonyloxypropynyl) starting compounds

is prepared in a similar manner from 17a-(3-hydroxypro-

the pynyl) compounds by treating these down to an arylsulfonyl chloride or alkylsulfonyl chloride, respectively. This reaction is suitably carried out in pyridine cg at approx. room temperature. Suitable arylsulfonyl chlorides for this purpose are 4-toluenesulfonyl chloride, benzenesulfonyl chloride, 4-bromobenzenylsulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 2-nitro-4-chlorobenzenesulfonyl chloride, mesitylenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride and 2,4,5- trichlorobenzenesulfonyl chloride. Suitable alkylsulfonyl chlorides are methanesulfonyl chloride, 3-chloropropanesulfonyl chloride and 1-hexadecanesulfonyl chloride.

An alternative method for preparing 3-hydroxy-propynyl compounds, which is particularly useful in the estrogen series, consists in ethynylating a 17-oxo starting compound. per se known methods, i.e. a treatment with potassium acetylide, whereby the 17a-ethynyi-178-hydroxy derivative is produced. Then the 17S_hydroxy group is preferably protected before further reaction, e.g. by forming the tetrahydropyran-2-yloxy or the tetrahydrofuran-2-yloxyether. ,With such a further reaction, the ethynyl group is built up in terms of the addition of a hydroxymethyl group as a replacement for the acid hydrogen. This is carried out by forming the ethynyl lithium salt (by treating the ethynyl derivative at room temperature with an equivalent amount of an ether solution of methyl, butyl or phenyllithium) and treating this compound with an equivalent amount or a slight excess of para-formaldehyde under weak refluxing in ether followed by hydrolysis, according to the method described by Schaap et al., in Ree. Trot. Chim. 34, 1200 (1965).

The procedures for preparing 3-halopropynylstercide compound are more fully described, e.g. in US Patent No. 3,029,261.

In the preparation of starting 17a-(3-substituted propynyl) derivatives in the 6,6-difluoroandrostene and -19-nor-androstene series, the preceding methods can be applied to the corresponding 6,6-difluoroandrost-4-ene-3 ,17-diones and 6,6-difluoro-19-norandrost-4-ene-3,17-diones and the 1S-alkyl derivs. In practice, the 6,6-difluoro group fpr-t into the precursor anirc3*"-4-f-r-3, 1^-dicnes and 19-nor-androst-4-en-3,17-diones or the precursor of i8 -alkyl derivatives. A method by which this can be carried out is described in US Patent 3,219-673. This method comprises treating a 3-acyloxy-5~fluoro-6-ketosteroid (which is known or can be prepared as described in the above-mentioned patent) with sulfur tetrafluoride, whereby the corresponding 3-acyloxy-5,6,6-trifluorosteroid is produced which can then be hydrolysed to the 3-hydroxy-536,6-trifluoro compound. This last compound can then be oxidized to the corresponding 3-keto-5,6,6-trifluoro derivative which is then treated with a dehydrofluorinating agent, eg aluminum oxide, whereby the 3-keto-A*-6,6-difluoro compound is obtained.

Another method by means of which these 6,6-difluorosteroids can be prepared involves forming an anoether twice in succession and treating this with perchloryl fluoride. Thus, the starting androst-4-ene-3,17-dione can be converted to its enol ether, after which this is treated with perchloryl fluoride so that the 3-keto-A^-6-fluoro derivative is formed. Can use the same procedure again with this compound, whereby the 3-keto-A h-6,6-difluoroderivatives are produced.

The starting 17a-(3-substituted-propynyl) compounds in the A^^^^^-and-rosatriene series are prepared from the corresponding 17"Oxo-.Ai,^10^'"L'1'-androstatriene. The latter compound is known and can be prepared by treating a 3_keto-A^10^-steroid ■ with bromine in a pyridine solution, whereby it is produced

i) 9(10)

corresponding 3-ketc-A''-diene, this is ketalized to the corresponding 3-ketal-A'^10'' '^"^-diene, this is epoxidized with a peroxy acid.,' after which the epoxidized product is treated with a strong acid , for example as indicated in US Patent 3-461,116. In the preparation of the 17-oxc-A^' ^lt3^'"^-"trilene compounds, reduction with lithium-aluminum-t-butoxide can be used , thereby producing 3,17-diol. This is acylated and the 3-acylat-17-ol is separated by chromatography. The 17-alcohol is then oxidized, for example with chromic acid, whereby the 17-one compound is produced which is then processed as described above.

In the preferred embodiments, desired other groups in any other positions in the molecule are introduced before carrying out the new principle reaction. One should preferably and appropriately protect the groups that can compete with or influence the principled reaction, or methods that lead to this principled reaction. Examples of such protection include forming the ketal or enol ethers of the 3-oxo function which can then be recreated later. Alternatively and in the preferred embodiments, the 3-keto function is not protected, after which the resulting 3P-hydroxy compound is reoxidized, e.g. with chromic acid in pyridine, manganese dioxide, etc. In the preferred embodiments, the principle reaction is carried out on the 17p-hydroxy or 17p-esterified hydroxy starting compounds.

In the estrogen series, a treatment of e.g. 17α-ethynyl-3»17P-diol derivative hydrated with a suitable carboxylic anhydride, e.g. acetic anhydride, in pyridine selectively give the 3-acyloxy-17p-hydroxy deriv. By using an acid anhydride in the presence of the corresponding acid and an acid catalyst, e.g. p-toluenesulfonic acid, gives the 3»17P~diacyloxy derivative. This diester can then be selectively saponified, e.g. by using a methanolic potassium bicarbonate solution, whereby the corresponding 3-hydroxy-17j3-aeyloxy derivative is obtained. Correspondingly, a prioritization can be carried out in a commonly known manner. Thus, a treatment with dihydropyran in the presence of an acid catalyst such as p-toluenesulfonic acid, p-toluenesulfonyl chloride, dinitrobenzenesulfonic acid or the like, in the corresponding tetra-hydropyran-2-yloxy derivative. A preparation of the mono-tetrahydro-pyranyl ether can be carried out by selectively protecting the other hydroxy groups, e.g. by an ester formation process, after which these ester groups can be alkaline hydrolysed after the formation of the ether, if this is desired. A preparation of the 3-thoxyderivative can e.g. is carried out by using diethylsulphate and potassium hydroxide in the usual known manner.

Similar conventional esterification and esterification methods can be used in the other series of starting compounds for the present invention. By e.g. preparation of the starting 3P»17P diacylate compounds for the present process, the 3>17-dioxo compound can be reduced and acylated with approximately a chemically equivalent amount of the acylating agent. The product mixture can then be chromatographed to isolate the 3β-acylat-17β-ol compound. This derivative can then be oxidized to the 3P_acylate-17-oxo compound. The Grignard method for introducing the etherified propynyl group at C-17a, as described above, is then used herein including the addition of a suitable acylation prior to normal work-up to produce the 3j3,17p-diacylate-17a-etherified propynyl compound. These compounds can be used as starting compounds or can be converted into other 17'-(3-substituted propynyl) starting compounds

parts r

The 3(3-, 178-diethers can conveniently be prepared by

first to prepare the 33,173-dietrene and following this preparation with the formaldehyde method for the preparation of 17a-(hydroxy-propynyl) compounds, as described above. These compounds can then be etherified with dihydrofuran, dihydropyran or 4-methoxy-5,6-dihydro-2H-pyran.

If a mixed ester-ether compound is desired, then the monoether can be prepared in a similar manner as described above for the preparation of the monoacylate. The Grignard method described above can then be used, followed by an acylation before normal processing. Alternatively, the monoacylate, prepared as described above, can be ethynylated at C-17a, after which the C-173 hydroxyl group is etherified. The formaldehyde method described above can then be used for the production of the corresponding 17a-(hydroxypropynyl) compounds, which can then be esterified as described above.

The terms "carboxylic acyl group" and "carboxylic acyloxy group" mean acyl and acyloxy groups which contain up to 12 carbon atoms and which can be straight, branched or cyclic. Said groups can be saturated, unsaturated, aromatic or optionally substituted with functional groups, e.g. hydroxy, alkoxy with up to 5 carbon atoms, acyloxy with up to 12 carbon atoms, nitro, aminc, halogen and the like. Representative esters are acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, (3 -chloropropionate, adamantoate, bicyclo{2-,2,2}.-octane-l-carboxylate,.. bicyclo{2,2,2}oct-2-ene-l-carboxylate,.. 4-methylbicyclo{2,2 . -heptyl, n-octyl, - isooctyl and the like. With the term "cycloalkyl group" as indicated above by R , for example, are meant groups such as cyclopentyl, cyclohexyl and the like, and usually contain from 3-8 carbon atoms.

The term "alkylsulfonyloxy" groups is understood to mean groups where the alkyl group is as defined above, preferably with from 1-6 carbon atoms.' The alkyl group can also preferably be substituted with halogen. The arylsulfonyloxy group is one where the aryl group is naphthyl, phenyl or a mono- or poly-substituted phenyl, and where the substituents may be selected from the group consisting of alkyl, alkoxy, halogen, nitro and the like.

The following examples illustrate the invention.

Example 1

A suspension of 5 g of lithium aluminum hydride in 100 ml of dry ether was heated under reflux for 1 hour. It was then cooled to room temperature and treated dropwise with stirring with 5 g of 3-ethoxy-17a-(3-tetrahydropyran-2'-yloxypropynyl)-estra~3,5-dien-17S-ol in 100 ml of dry ether. The reaction mixture was stirred and heated under reflux for 2.5 hours. The excess reagent was then decomposed at 0°C using acetone and a saturated sodium sulfate solution and solid sodium sulfate. The mixture' was then filtered, washed with methylene chloride and evaporated to dryness, whereby 3-ethoxy-17a-propadienylestra-3,5-diene-173-01 was prepared which was hydrolyzed with HCl in methanol (100 ml) at room temperature in " over 15 min. The mixture was then poured into ice water, extracted with methylene chloride, washed with water, dried and evaporated to dryness, whereby 2.5 g of 17a-propadienyl str-4-ene-17£-ol-3- on, mp 137-140°C, which was further purified by chromatography and eluted with ethyl acetate/hexane 40/60.

Example- 2

A mixture of 1 g of 17α-(3-tetrahydropyrar-2'-yloxy-propynyl)-estra-4,9(10),11-trien-17S_ol-3-one, 25 ml of dry benzene,

5 ml of ethylene glycol and 50 mg of p-toluenesulfonic acid monohydrate were boiled

under reflux for 16 hours using a water separator. The reaction mixture was washed with aqueous sodium bicarbonate solution and water, dried and evaporated to dryness to give 3,3-ethylenedioxy-17a-(3-tetrahydridpyran-2'-yloxypropynyl)-estra-4,9(10),11-triene -173-ol which was recrystallized from acetone:hexane.

A solution of 1 g of 3,3-ethylenedioxy-17a-(3-tetra-hydropyran-2'-yloxypropynyl)-estra-4,9(10),11-trien-17B-ol in 50 ml of tetrahydrofuran was added during of 30 min. to a stirred suspension of 1 g of lithium aluminum hydride in 50 ml of anhydrous tetrahydrofuran, and the mixture was refluxed for 2 hours. It was then slowly added 5 ml of ethyl acetate and 2 ml of water. Sodium sulfate was then added, the mixture filtered and the solid collected and washed with hot ethyl acetate. The combined organic solutions were evaporated, whereby a 3,3-ethylenedioxy-17a-propadienylestra-4,9(10),11-trien-17B-ol product was obtained which can be further purified by cmcrystallization from acetone:hexane.

A mixture of 0.5 g of 353_ethylenaicksy-17a-propadienyl-estra-4,9(10),11-trien-17B-ol in 30 ml of acetone and 50 mg of p-toluenesulfonic acid was left at room temperature for 15 hours. The mixture was then poured into ice water and extracted with ethyl acetate. The combined extracts were washed with water to neutrality, dried over sodium sulfate and evaporated to dryness. The residue was treated with ether, whereby 17a-propadienyl-estra-4,9(10),11-trien-173-ol-3-one was precipitated, an amorphous solid, [a]D -48° (CHClj) ,

\naks 240> 3k0 nm> £ 3>8^> 4'3)> vmax 3500> 3^00' 195°' 1640, 1560 cm which was recrystallized from acetone:hexane.

Example 3

1 g of lithium di-(2-methoxyethoxy) aluminum hydride was dispersed in 50 ml of diethylene glycol methyl ether at room temperature.

A steroidal solution of 1 g. 3-Methoxy-17ct-(3-p-tolylsulfonyl-'oxy-propynyl)-estra-1,3S5(10)-trien-176-ol dispersed in 50 ml of diethylene glycol methyl ether was then added to the hydride dispersion. The addition was carried out in portions over 30 min. at room temperature and with stirring. The mixture was then heated to its boiling point and held under reflux conditions for approx. 2 hours. Then 5 ml of ethyl acetate was slowly added followed by 2 ml of water. Sodium sulfate was then added and the entire mixture filtered. The. collected solid was washed with hot ethyl acetate. The combined organic solutions were evaporated, whereby 0.1 g of 3-me<toxy>-<17>ct<-propadienylestra-1>,<3-,5>(<10>)<-trien-17> was produced S<->ol<->prc<->duct, sm.p. 130-132°C, which can be further purified by recrystallization from acetone:hexane.

If you repeat the above-mentioned procedure, except that you carry out a work-up as stated in example 1, i.e. a reagent decomposition at 0°C, then 3-methoxy-17a-propadienylestra-1,3,5(10)-trien-173-ol is produced in a 5% yield.

Example 4

A solution of 1 g of 6,6-diflucr-17a-(3~fluoropropynyl)-estr-4-ene-176-cl-3-one in 50 ml of tetrahydrofuran was in the course of 30 min. added a stirred suspension of 1 g of aluminum hydride in 50 ml of diethyl ether, and the mixture was refluxed for 2 hours. To the mixture was then added 5 ml of ethyl acetate and 2 ml of water. Sodium sulfate was then added and the mixture filtered, and the solid washed with hot ethyl acetate. The combined organic solutions were evaporated, whereby the 6,6-difluoro-170-propadienyl-estr-4-ene-33,173-diol product was produced, which can be further purified by cross-crystallization from acetone hexane.

The above procedure was repeated using 6,6-difluoro-17a-(3-tetrahydropyran-2'-yloxypropadienylestr-4-en-17S-ol-3-one as starting material with the same result. 1 g of 6,6-difluoro- 17ot-propadienyl str-4-ene-3B,173-diol in 100 ml of chloroform which had been distilled over calcium chloride was stirred for 1 18 hours at room temperature to which was added 10 g of freshly precipitated manganese dioxide.The inorganic materials were then removed by filtration and washed with hot chloroform , after which the filtrate and the washing solution were evaporated to dryness, whereby 0.6 g of 6,6-difluoro-17a-propadienylestr-4-ene-173-ol-3-one, a non-crystalline solid, was produced, vCHp13 3610, 1960 and 1690 cm"1, AEt?H 227 nm ' max 5 max (e 11,200) m/e 348.1908, calculated for C21H20°2F2 is 348.1908, which can be further purified by recrystallization from acetone:hexane.

Example 5

A solution of 1 g of 17o-(3-bromopropynyl)-estr-5(10)-en-173-ol-3-one in 50 ml of tetrahydrofuran was in the course of 30 min. added a stirred suspension of 1 g of lithium di-(2-methoxyethoxy) aluminum hydride in 50 ml of anhydrous tetrahydrofuran, and the mixture was refluxed for 2 hours. The mixture was then slowly added with 5 ml of ethyl acetate and 2 ml of water. Sodium sulfate was then added, the mixture filtered, and the solid washed with hot ethyl acetate. The combined organic solutions were evaporated, whereby 17a-propadienyl str-5(10)-ene-33,173-diol was precipitated as can. further purified by recrystallization from acetone:hexane.

An oxidation gives 0.2 g of 17-propadienyl str-5(10)-ene-

The 17 -ol-3-one product, m.p. 134.5-136°C.

Example 6

A solution of 1 g of 17-(3-chloropropynyl)-17-hydroxy-estr-4-en-3-one in 50 ml of tetrahydrofuran was in the course of 30 min. added a stirred suspension of 1 g of lithium aluminum hydride in 50 n of anhydrous tetrahydrofuran, and the mixture was boiled under reflux conditions for 2 hours. To it was then added 5 ml of ethyl acetate and 2 ml of water. Sodium sulfate was then added, the mixture filtered and the collected solid washed with hot ethyl acetate. The combined organic solutions were then evaporated, whereby 0.12 g of 17a-propadienyl str-4-er.-33sl7S-diol product was precipitated, m.p. 58-6C°C, which can be further purified by recrystallization or. from acetone:hexane.

A solution of 6 g of 17α-propadienyl-estr-4-ene-33,173_

diol in 120 ml of pyridine was added to a mixture of 6 g of chromium trioxide in 20 ml of pyridine. The reaction mixture was left at room temperature for 15 hours, diluted with ethyl acetate and filtered through celite diatomaceous earth. The filtrate was washed with water, dried and evaporated to dryness, whereby 4.2 g of 17α-propadienylestr-4-en-173-ol-3-one were precipitated, m.p. 137-140<c>C, which can be further purified by recrystallization from acetone:hexane.

Example 7

In accordance with the methods stated above, the following was carried out.

From 17a-(3-chloropropynyl)-173-acetoxy-18-methylestr-4-en-3-one, the corresponding 17a-propadienyl-176-acetoxy-18-methylestr-4-en-3-one product was prepared, m.p. . 152-153,

By replacing 17α-(3-chloropropynyl)-176-aceto>sy-18-methylestr-4-en-3_one with 17α-(3-chloropropynyl)-173-hydroxy-16-nethylestr-4-en-3_one,. 17α-propadienyl-17S-hydroxy-18-methylestr-4-en-3-one is produced, m.p. 148-150°C.

Example 8

A mixture of 1 g of 17α-propadienyl-173-acetoxyestr-4-en-3B~ol, 4 ml of pyridine and 2 ml of acetic anhydride was left at room temperature for 15 hours. The mixture was then poured into ice water and the solid formed was collected by filtration, washed with water and dried to give 0.8 g of 33,173-diacetoxy-17a-propadienyl-estr-4-ene, an oil, [ajj- -11° (CHCl-j), which can be further purified by recrystallization from acetone:hexane.

Example 9

The corresponding C-3-substituted derivatives of the 17α-propadienyl products in the estrogen series were prepared in accordance with the above procedures using the 3-hydroxyl derivative as starting compound. This starting compound can be prepared according to the present principle reaction by ordinary hydrolysis of the protecting group or groups, such as a tetrahydro-pyran-2'-yloxy group by means of acid hydrolysis. A representative 3-substituted compound in this series thus prepared is: 6,6-difluoro-17α-propadienyl-18-methylestr-4-ene-17S-ol-3-or;, m.p. 164-165"'C.

Claims (2)

1. Process for the production of 17a-propadienyl steroids with the formulas: where R<1> is hydrogen or a lower alkyl group with 1-3 carbon atoms, R 2 is hydrogen, tetrahydrofuran-2-yl, tetrahydro-pyran-2-yl, 4-methoxytetrahydropyran-4-yl, or a carboxylic acyl group with up to 12 carbon atoms, R<3> is an oxo group H 6 or the group R 0 y, where R is hydrogen, tetrahydrofuran-27yl, tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl or a carboxylic acyl group with up to 12 carbon atoms, R 1 is hydrogen or methyl, and R 5 is hydrogen, a lower alkyl group of 1-8 carbon atoms, cycloalkyl, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl or a carboxylic acyl group of up to 12 carbon atoms, characterized in that a 17a-(3-substituted propynyl)-steroid, where the substituent is tetrahydrofuran-2-yloxy,' tetrahydropyran-2-yloxy, 4-methoxytetrahydropyran-4-yloxy, halogen, alkylsulfonyloxy or arylsulfonyloxy, is treated with a aluminum hydride reagent, suitably in an organic liquid reaction medium and at a temperature of about 20-120°C. 2. Method according to claim 1, characterized in that lithium aluminum hydride is used as aluminum hydride reagent.