CA1069118A - Difluoresteroids and processes for their manufacture - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Novel 18,18-difluorosteroids are disclosed of the general formula (Ia) wherein R3 denotes hydrogen or lower alkanoyl, R4 denotes hydrogen or lower aliphatic hydrocarbon, and St represents a radical of the partial formula:

or (ST1) (St2) (St'2)

Description

- - ~069~

The present invention relates to a hitherto un-known group of compounds, the 18,18-difluorosteroids, and, . in particular, to processes for the manufacture of the compounds of the general formula St F ~ --R4 (Ia) .,, ~ .

~` - wherein R3 denotes a hydrogen atom or a lower alkanoyl ` group and R4 denotes a hydrogen atom or a lower aliphatic :~ hydrocarbon radical, especially a lower alkyl radical, above all the methyl radical and ethyl radical, or the ethinyl radical, and St denotes a radical of the partial formula - R5 ~ R60 ~ 'R7 ~ R7 (Stl) (St2) (St'2) R ~ .

~ UO ~ (SC3~ ;

: wherein R5 denotes the oxo group or a hytrogen atom con-jointly with an esterified hydroxyl group, or especially . , ,. ' q~-,,, . . . :

- . , . . . - - - . -':, - . . . : -- . - - ~ . . - , .. : . .. . . .

,. . ~ ;~

. ', ' . ~ ,: '~ ' ' ' ' . : ~
. ~ - . -,. .- : - , , ~ . ~.: : , -- . : ., -, . ., - .. .
, ` 1069118 .

with a free hydroxyl group, or denotes two hydrogen atoms, R6 denotes a hydrogen atom or a lower alkyl group, espe-cially the methyl group, R7 denotes a hydrogen atom or the methyl group, and R denotes a hydrogen atom or the methyl group, it being possible for an additional 1,2-double bond also to be present in compounds of the partial formula St in which R is the methyl group.
Wherever it is used in connection with an organic radical, the term ~'lower" designates a corresponding radical with at mo8t 7, but preferably with 1 to 4, carbon atoms.
A lower alkyl radical is, for example, a n-propyl, ~-propyl, n-butyl, i-butyl, sec.-butyl or tert.-butyl radical or a branched or preferably straight-chain pentyl, hexyl or ~eptyl radical, but above all an ethyl or methyl radical.
A lower aliphatic hydrocarbon radical is to be regarded as a lower alkyl radical, for example one of those already mentioned, or an analogous radical which in addition contains one or two multiple bonds, that i8 to say double bonds or acetylenic bonds, such as, or example, a lower alkenyl, lower alkinyl and allenyl radical, for example a vinyl, allyl, meth-allyl, propargyl, hexadiinyl and, above all, ethinyl radical.
An esterified hydroxyl group is derived, in par-ticular, from a carboxylic acid customary in steroid chemi-stry, for example a monocarboxylic acid with at most 18 carbon atoms, such as aliphatic carboxylic acids, especially .. .. . .. .. ~ .

: .
' ' ~ .

10691~8 from formic acid or a lower alkanecarboxylic acid, the lower alkyl radical of which is one of those mentioned above, primarily propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, oenanthic acid and diethyl-acetic acid and, above all, caproic acid, trimethylacetic acid and acetic acid.
e new 18,18-difluorosterolds according to the Invention can be used as intermediates for the synthesis of valuable pharmaceutical active substances, especially for honmone therapy and for fertility control, and also a8 additives in animal feeds. A number of the steroids, for example the com-pounds singled out for special mention hereinafter, at the same time themselves exhibit a biological activity and, accor-d~ngly, can be used direct as acti~e substances in the above-mentioned fields of applicaticn.
. . , , -- .
Compounds to be singled out, because of their advan-tageous biological properties, from the compounds of the formula Ia are those in which St represents a radical of the partial formula Stl. These compounds are distinguished as highly active sex hormones. On the one hand, they have a central action in that they block the secretion of pituitary gonadotrophins; on the other hand, they also have a peri-pheral action on the male and the female sexual functions, as can be demonstrated by animal experiments. Because of these advantegeous biological properties, the compounds .. .. " . . .. , . , ~ . . ..

~0 69 ~ 18 can be used in medicine for all indications involving sex hormones, but especially as preparations for inhibiting gonadotrophin secretion and/or for controlling fertility.
Compounds to be singled out particularly are 17~-acetoxy-18,18-difluoro-oestr-4-en-~-one, whlch in a dose of 0.01 mg/animal -~
(capon , comb test, local application) exhibits a marked andro-genic activity and in a dosage range of from 0.01 to 0.1 mg/kg (rat , ovulation test, subcutaneous administration) inhibits ovulation, and 17a-ethinyl-18,18-difluoro-l?~-h~ o~ 3-one, whlch in a dosage range of from 0.03 to 0.3 mg1kg (rabbit , Clauberg test, perorally) exhibits a distinct gestagenic . . .
ac~ivity and in a dosage range of from 0.3 to 1 mg/kg (rat , ovulation test, perorally) inhibits ovulation.
Compounds which should also be mentioned because of their advantageous biological properties are those amongst the compounds of the formula Ia in which St represents a .
radical of the partial formula St2.
These compounds are also distinguished as highly active sex hormones. They have a central action and greatly inhibit the secretion of pituitary gonadotrophins. In addi-tion, they also have a strong peripheral, especially oestro-genic activity, as can be shown by animal experiments.
Because of these advantageous biological properties, they can be used as therapeutic preparativns in medicine for all - ' ' ~ .
... ... .. . . . . . .
. .: .:, - . .
':~,, ' ' ~ . -., . . , ~ . , .

....
, ,, the indications usual for oestrogens, but especially to inhibit gonadotrophin secretion andtor to control fertility.
The 18,18-difluorosteroids according to the in-vention are obtained according to a novel chemical process, which is characterised in that in a corresponding 17-ketone of the general formula III
'~:HF2 St ~ ~ (III) .
where~n S~ has the meanings indicated for Stl, St2, St'2 and St3, the 17-oxo-group is reduced to a hydroxyl group, optionally with a simultaneous introduction of a lower ;~ aliphatic hydrocarbon radical into the 17a-position, and, if a compound of the formula Ia is required in which a hydroxyl group in the 3- and/or 17-position is in an esteri-fied form, a resulting product having a corresponding free A~ hydroxyl group is esterified.
h~
The reduction of the 17-oxo group to the hyd-ccyl group is carried out in a manner which is in itself known and advantageously diborane or complex hydrides, especially those of aluminium or boron with an alkali metal or alkaline earth metal, such as, for example, sodium aluminium hydride, calcium borohydride and lithium borohydride, but especially lithium aluminium hydride and above all sodium borohydride, or :
~ . . .

: . . - - .

. . , .. . ~ .. ~ -.

.. . : . . . .. .
- . ,:
- . .
.
. ~ -. .. . ... .

10~9118 derivatives thereof in which one or more hydrogen atoms are replaced by lower alkoxy radicals, such as sodium methoxy-borohydride and especi~lly Iithium tri-tert.-butoxy-aluminium hydride, are advantageously used for this purpose. The choice of the solventandcEthe reduction conditions depends on the reducing agent used and is in accordance with the generally known principles. If a selective reduction of the 17-oxo group is required, the other oxo groups are protected temporarily as ketals or enol ethers; when a 3-oxo-~4-,grou-ping is present, the procedure can also be such that this grouping is reduced simultaneously and then selectively dehydrogenated, for example with manganese dioxide, back to the 3-oxo-~4-grouping.
The reduction of the 17-oxo group with simulta-neous introduction of a lower aliphatic hydrocarbon radical, for example one of those mentioned initially, is carried out in a manner which is in itself known by reacting the 17-oxo compound with a corresponding organo-metallic compound.
If the hydrocarbon radical to be introduced is a lower alkyl radical, a ¢rignard compound, for example a lower alkyl-magnesium halide, such as methylmagnesium bromide or methylmagnesium iodide, or lower alkyllithium, such methyl-lithium, is preferred as the organometallic compound; if a l-alkinyl radical, especially the , ., ., .; . . ~

, . . . . - - - ~ . .
.
- . - , . . . , - , . -. '' : . .. - . ,:. '.... . . ~ .~ ~

0 69 il8 ethinyl radlcal, is to be introduced, a oorrespondlng al~ali metal compound, for example sodium acetylide or potassium acetylide or, in particular, lithium acetylide, is advantageously used. In the latter case it is particularly advantageous to use lithium acetylide in the form of lts complex with ethylenediamine. Also in this case, the other oxo groups must be protected in a manner analogous to that described above for the selective reduction.
The ketalisation and the formation of enol ethers, which are to be carried out, if necessary, in order to protect the oxo groups, are also effected ~
in a manner which is in itself known, especially under the conditions of acid catalysis and optionally using dehydratin~
agents or azeotropic distillation. For ketalisation, for example, lower alkanols, such as methanol or ethanol, and especially a- and ~-glycols, such as 1,2- or 1,3-propanediol and 1,2_ or 2,3-butanediol, and, above all, ethylene glycol, .. . .
or reactive derivatives of these alcohols, such as acetals or ketals, especially those in which the carbonyl component is readily volatile, such as, for example, 2,2-dimethyl-1,~-dioxolane, are used. Corresponding thioketals are obtained analogously, but starting from the sulphur analogues of the abovementioned alcohols, above all from l,?-ethanedithiol or a reactive derivati~e thereof. - In order to form the enol ethers, an ortho-ester of a lower alkanol, especially of methanol or ethanol, with a lower aliphatic carboxylic acid, , .

,. , , :, : , :, - : -: . . . . : :

: -~0 69 11 8 _ 9 _ .`~ ' .
` especially formic acid, is preferably used as the reagent;
particularly preferred reagents are methyl orthoformate and, above all, ethyl orthoformate. In the case of ; an oxo group conjugated with a double bond, the formation of the ketal or enol ether ~ay also be accompanied by a shi~t of the double bonds, for example in the case of the 3-oxo-~4 ~ grouping the 4,5-double bond migrates into the 5,6-position.
; The subsequent liberation of the temporarily protected oxo groups in the resulting process products is carried out in a manner which is in itself known, preferably by hydrolysis. Both enol ethers and ketals are prefer-ably hydrolysed under the conditions of acid catalysis in the presence oP an inorganic acid, for example sulphuric acid, or a hydrogen halide acid, such as hydrochloric acid, hydrobromic acld or hydriodic acid, or of an organic acid, for example a sulphonic acid, such as p-toluenesulphonic acid cr sulphosali-cylic acid, or of a strong carboxylic acid, such as oxalic acid or formic acid.
The subsequent esterification or etherification of hydroxyl groups in the resulting compounds is also effected ln a manner ~rhich is in itself kno~. For esterification, for example, the compound to be esterified is treated with an excess of the aoid itself, such as with formic acid, or with a reactive derivative thereof, for example with a derivative of one of the abovementioned acids, especially with an .~ . .
.; . .
~ ' ' ' - .
,~ .

.. ..

. - , : . . :
.
.
.. , , .. , ~0 69 1 1 8 .

anhydride or acid halide, advantageously in the presence of a tertlary base, rsuch as pyridine, quinollne or N-ethyl-piperldine; For etherification, for example, thc com~ounds to be etherified are treated with reactive derivatives of alcohols, for example with esters of strong acids, such as ~alides, sulphates of sulphonic acidesters~ it being possible to use, in particular, one of the above mentioned alcohols as the alcohol component. Preferably, the reaction is carried out in the presence of basic agents.
Those compounds of the formula Ia in which St has the meaning of St2 can also be prepared advantageously in a manner which is in itself known, for example as described below, by aromatisation of a resulting corresponding compound of the formula Ia, in which St represents a radical of the partial formula St2 asdefined above, and, if a compound is required in which R6 is lower alkyl, by subsequent etheri-fication of a resulting 3-hydroxy compound at the 3-hydroxyl in a manner describe above.
The aromatisation is carried out in a manner which is in itself known by reacting a l9-nor-~4-3-oxo compound, optionally in the form of a 3-enol ether thereof, with a .. ..
~ quinone, such as chloranil or especially 2,3-dichloro-5,6-; dicyano-1,4-benzoquinone, by which means, by rearrangement .
. ~ .

.: : , . . : . . . . ....... .

r~

- 11 - , of the 3-oxo-1,4-diene grouping first formed, aromatisation of the A ring can take place in the same step, the 3-hydro-xy-1,3,5(10)-triene grouping being formed.
Alternatively, the compounds of the formula Ia wherein St has the meaning of Stl in whi-ch R5 is an oxo group can be obtained when in a corresponding resulting compound of the formula Ia, wherein St represents a radical of the partial formula St3 as defined above, the 3-hydroxyl group is oxidised in a known manner, for example as described below, especially by the Oppenauer oxidation, to the 3-oxo group, the double bond being simultaneously shifted into the 4,5-position.
Oxidising agents are compounds of 6-valent chromium, ~uch as chromium trioxide, chromic acid and the alkali metal salts thereof,Lower alkanecarboxylic acids, such as acetic acid or proplonic acid, or pyridine or acetone, optionally diluted with a halogenated lower alkane, such as dichloro-methane or chloroform, and/or in the presenoe o~ ~queous sulphurlc acid, ad~antageously are use~ às the ~eaction ~ medium.Apreferred alternative is the Oppenauer oxldatlon, that is to say oxidation with a ketone, such as acetone or cyclohexanone, under the catalytic action o~ an aluminium lower alkoxide, such as aluminium isopropylate; .
.

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' .. . : . . . ' , :
. . - ~
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: . . . . . ... . . . . .
, . . ~. .
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- - 1069~18 the Oppenauer oxidation is particularly advantageous in that the double bond in the 5,6-position migrates spontaneously into the 4,5-position. i -The invention also relate~ to those embodiments of the above processes in which a compound obtained as an intermediate at any stage is used as the starting material and the missing ~teps are carried out or in which a starting material is fonmed under the reaction conditions.
The starting materials of formula III for the pro-cesses of the present invention are manufactured in a manner which is described in our co-pending Canadian Patent Appli-cation Ser. No. 232,334. Appropriately, those starting ma-terials which contain the substituents mentioned particularly above, and especially those starting materials which lead to the final products described specifically or highlighted by ! formulae herein, are used.

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.

m e present invention also relates to the production of pharmaceutical preparations, and of contraceptives for humans and mammals, which contain the new pharmacologically active substances, described above, of the present invention as active substances, together with a pharmaceutical excipient.
Organic or inorganic substances which are suitable for enteral, for example oral, or parenteral administration or for topical application are used as the excipients. Substances which can be used to form the excipients are those which do not react with the new compounds, such as, ~or example, water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gum, polyalkylene glycols, white petrol-eum jelly, cholesterol and other known medicinal excipients.
m e pharmaceutical preparations can be in the solid form, for example as tablets, dragees or capsules, or in the liquid or semi-liquid form as solutions, suspensions, emulsions, oint-ments or creams. Optionally, these pharmaceutical prepara--- tions are sterilised and/or contain auxiliaries, such as pre-servatives, stabilisers, wetting agents or emulsifiers, salts to regulate the osmotic pressure or buffers. They can also contain other therapeutically valuable or biologically active substances.
me following Examples describe the invention in more detail, but do not limit it to what is described therein.
The tempera~ures are given in degrees Centigrade.

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Example 1 After adding 22 ml of a 10% strenght potassium hydroxide solution, a solution of 2.3 g of 18,18-difluoro-androst-5-ene-3~,17~-diol diacetate (crude product) in 130 ml of methanol is stirred for 1 hour at room temperature, whilst passing nitrogen through the solution. me reaction mix-ture is then concentrated to about 60 ml in an aspirator vacuum and taken up in ethyl acetate and the mixture is washed with 1 N hydrochloric acid and with water until neut-ral, dried and evaporated in an aspirator vacuum. The crude .18,18-difluoro-androst-5-ene-3~,17~-diol is suspended, with-out purification, in 80 ml of toluene, the suspension 7S
treated with 8 ml of cyclohexanone and 2.2 g of aluminium iso-propylate and the mixture is refluxed for 45 minutes with stirring. The cooled reaction mixture is worked up by diluting it with ethyl acetate and washing it successively with satura-ted Seignette salt solution (potassium sodium tartrate solu-tion) and with water. The washings are further extracted with ethyl acetate and the organic phases are dried and evaporated in an aspirator vacuum. The amorphous residue is then chromato-graphed over 100 times the amount by weight of silica gel.
Elution with a mixture of hexane/ethyl acetate(3:1) gives successively, in approximately equal amounts by weight, 18,18-difluoro-androst-4-ene-3,17-dione, which after recrystalli-sation from acetone/hexane melts at 161-163C, and 18,18-di-.

.. . . . .. .
. ~ . . . . . . - . .
- - .

. . . . -, . . . . . -... : . .. . . ~ . - - , .
- ~ ' : . ' - -... . . - . : .' : - , :

69 ~ ~ 8 uoro-17~-hydroxy-androst-4-en-3-one o~ melting point 183-184C
(recrystallised from acetone/hexane).
Example 2 500 mg of 18,18-difluoro-androst-4-ene-3,17-dione are dissolved in 20 ml of dioxane and, after adding 1 ml of orthoformic acid ethyl ester and 30 mg of p-toluenesulphonic acid, the mixture is stirred ~or 8 hours at room temperature.
The reaction mixture is then poured into.water (containing traces of pyridine) and extracted twice with ethyl acetate :~
and the extracts are washed until neutral, dried and evapora-ted in an aspirator vacuum. The crude amorphous enol ether (3-ethoxy-18,18-difluoro-androsta-3,5-dien-17-one) is dis-solved direct in 30 ml of absolute ether and the solution is added dropwise to an ethereal solution of methyl magnesium iodide prepared from 300 mg of magnesium turnings and an equi-valent amount of methyl iodide, whilst stirring and cooling.
The reaction mixture is refluxed for 2 hours and then worked up in the customary manner. ~le crude carbinol is subjected to hydrolysis direct, without purification.
For this purpose, the compound is dissolved in 10 ml of 66%
~trength acetic acid and the solution is stirred for 2 hours at 30C. It is then diluted with water and extracted with e~hyl acetate and the extracts are washed until neutral (twice with saturated sodium bicarbonate solution and with water), dried and evaporated in an aspirator vacuum. Chroma-- .

: . . . .-, - . -, : .,-; .. . - .
, . - :
:, . ., , ,. ... ~. . ...

tography of the crude product over 100 tires the amount by weight of silica gel (system: hexane/ethyl acetate, 3:1) gives 18,18-difluoro-17~-hydroxy-17-m~thyl-androst-4-en-3-one.
Example 3 250 mg of 18,18-difluoro-17~-hydroxy-oestr-4-en-3-one are dissolved in 1 ml of pyridine, 1 ml of acetic anhydride is added to the solution and the mixture is left to stand for 15 hours at room temperature. me reaction mixture is then poured into ice water, the mixture is extracted twice with ethyl acetate, washed until neutral, dried~and evaporated in an aspirator vacuum. After one crystallisation oE the crude product from ether/hexane, pure 18,18-di1uoro-17~-hydroxy-oestr-4-en-3-one acetate of melting point 108-110C is ob-tained.
Example 4 280 mg of 18,18-difluoro-oestr-4-ene-3,17-dione, 10 ml of dioxane, 0.5 ml of ortho~o~ic acid ethyl ester and 16 mg o~ p-toluenesulphonic acid are stirred for 6 hours at room temperature, li6ht being excluded. me reaction mixture is poured into 40 ml of water (containing 4 drops of pyridine), the mixture is extracted twice with ethyl acetate and the organic layer is washed with water and a saturated sodium chloride solution until neutral, dried and evaporated in an aspirator vacuum. ~le resulting amorphous 3-ethoxy-18,i8-difluoro-oest~3,5-dien-17-one is then dissolved in 6 ml of dioxane and the solution is added dropwise in the course of ..
' --',,, ; , ' .
20 minutes to a solution, which is saturated with acetylene, of 1.8 g of lithium ace~ylide-ethylenediamine complex in 18 ml of diox~ne, whilst at the same time passing acetylene through the solution. The reaction mixture is then stirred at room temperature for a further 15 minutes and saturated ammonium chloride solution and ethyl acetate are then added with coo~ing and the organic phase is washed successively with 1 N hydrochloric acid and with a saturated sodium chloride solution, dried and evaporated in an aspirator vacuum. In order to dissolve the resulting yellowish amorphous residue in 5 ml of tètrahydrofurane, 2.5 ml of a 3:7 mixture of concen- -trated hydrochloric acid and water are then added and the mix-ture is stirred for 1 hour at room temperature. After adding ethyl acetate, the organic layer is washed with sodium bicar-bonate solution and water until neutral (subsequent extraction with ethyl ace~ate)-, dried and evaporated in an aspirator ~-vacuum. The residue is chromatographed over 100 times the amount of silica gel, using hexane/ethyl acetate (2:1) as the eluant, to yield 18,18-difluoro-17-hydroxy-19-nor-17a-pregn-4-en-20-in-3-one (17~-ethinyl-18,18-difluoro-19-nor-testosterone), which after recrystallisation from methylene chloride/hexane melts at 244-252C.
In spectrum: 3550, 3280, 1670, 1620 and 1055 cm 1.
NMR spectrum: 2.63 ppm, singlet, (C-21), 5.84 ppm, broads~et (C-~), 6.13 ppm, triplet, JHF = 54 Hz (C-18).

.
.

, - ~ . . .. . . . .

... . - ~ .
. . .

~ 10 69 1 1 8 Example 5 A solution of 300 mg of 18,18-difluoro-3-methoxy-oestra~,5(10)-trien-17-one in 12 ml of dioxane is added dropwise in the course of 30 minutes to a solution, saturated with acetylene, of 1.5 g of lithium acetylide-ethylenediamine complex in 10 ml of dioxane, whilst at the same time passing acetylene through the solution. m e reaction mixture is stirred at room temperature for a further 60 minutes and treated, whilst cooling, with saturated ammonium chloride ~olution and with ethyl acetate. m e organic phase is washed successively with 1 N hydrochloric acid and with a saturated sodium chloride solution, dried and evaporated in an aspirator vacuum. The residue is chromatographed over silica gel with a mixture of hexane/ethyl acetate (9:1) as the eluant afording 17-ethinyl-18,18-difluoro-3-methoxy-oestra-1,3,5 (10)-trien-17~-ol, which after recrystallisation from acetone/
hexane has a melting point of 167-168C.

.. . .

,. . -, . ~
'' . - ~ ~

Claims (20)

WHAT WE CLAIM IS:

1. Process for the manufacture of 18,18-difluoro-steroids of the general formula (Ia) wherein R3 denotes a hydrogen atom or a lower alkanoyl group and R4 denotes a hydrogen atom or a lower aliphatic hydro-carbon radical, and St represents a radical of the partial formula , , or (St1) (St2) (St'2) (St3) wherein R5 denotes the oxo group or a hydrogen atom conjoint-ly with an esterified or free hydroxyl group, or denotes two hydrogen atoms, R6 denotes a hydrogen atom or a lower alkyl group, R7 denotes a hydrogen atom or the methyl group, and R denotes a hydrogen atom or the methyl group, it being possible for an additional double bond to be present in compounds of the partial formula St1 in which R is the methyl group, characterised in that a) in a corresponding 17-ketone of the general formula (III) wherein St has the meanings indicated above, the 17-oxo group is reduced optionally with a simultaneous introduction of a lower aliphatic hydrocarbon radical into the 17a-position, and subsequently, in order to obtain 2 compound of the for-mula Ia in which a hydroxyl group is in an esterified form, a resulting compound having a free hydroxyl group is esteri-fied, or b) in order to obtain a compound of the formula Ia, in which R3 and R4 have the above meaning and St has the meaning of St2, a corresponding resulting compound of the formula Ia in which St represents the radical St?, or a 3-enol-ether thereof, is aromatised by reacting with a de-hydrogenating quinone and, if a compound is required in which R6 is lower alkyl, the resulting compound having a free hydroxyl group is etherified, or c) in order to obtain a compound of the formula Ia in which R3 and R4 have the above meanings and St represents the radical St1 in which R5 is an oxo group, a corresponding resulting compound in which St represents the radical St3 is oxidised with a simultaneous shift of the double bond into the 4,5-position.

2. Process according to Claim 1a, characterised in that the reduction is carried out with a complex hydride of boron or aluminum to give a product in which both R3 and R4 are hydrogen.

3. Process according to Claim 2, characterised in that the reduction is carried out with lithium aluminum hydride or sodium borohydride.

4. Process according to Claim 1, characterised in that the oxo group in a .DELTA.4-3-oxo grouping in a starting material is reduced simultaneously to a 3-hydroxyl group.

5. Process according to Claim 4, characterised in that the resulting 3-hydroxyl group is re-oxidised selec-tively to regenerate the .DELTA.4-3-oxo grouping.

6. Process according to any one of Claims 1-3, characterised in that any 3-oxo group present in the star-ting material is temporarily protected during the reduction.

7. Process according to Claim 1a, characterised in that the reduction is carried out with a simultaneous in-troduction of a lower aliphatic radical by reaction with a corresponding organo-metallic compound, any 3-oxo group present in the starting compound being temporarily protected.

8. Process according to Claim 7, characterised in that a methylmagnesium halogenide is used as the organo-metallic compound in order to introduce methyl as the radical R4.

9. Process according to Claim 7, characterised in that an alkaline metal acetylide is used as the organometallic compound in order to introduce ethynyl as the radical R4.

10. Process according to any one of Claims 7-9, characterised in that the 3-oxo group is temporarily pro-tected as a lower alkyl 3-enol-ether.

11. Process according to Claim 1b, characterised in that the aromatisation is carried out with 2,3-dichloro-5,6-dicyano-benzoquinone.

12. Process according to Claim 1c, characterised in that Oppenauer oxidation is applied in order to dehydro-genate the hydroxyl group in the compound of the partial formula St3.

13. Process according to Claim 1, characterised in that a starting 17-oxo compound is selected so as to pro-duce a compound of the general formula 1A

(IA) wherein R denotes a hydrogen atom or the methyl group, R3 denotes a hydrogen atom, R4 denotes a hydrogen atom or a lower aliphatic hydrocarbon radical, and R5 denotes the oxo group, it also being possible in a compound in which R is the methyl group for an additional 1,2-double bond to be present.

14. Process according to Claim 1, characterised in that a starting 17-oxo compound is selected so as to pro-duce a compound of the general formula (IB) (IB) wherein R3 denotes a hydrogen atom, R4 denotes a hydrogen atom or a lower aliphatic hydrocarbon radical, and R6 and R7 each denotes a hydrogen atom or the methyl group.

15. Process according to Claim 1, characterised in that a starting 17-oxo compound is selected so as to pro-duce a compound of the general formula (IC) (IC) wherein R is hydrogen or methyl, R3 is hydrogen and R4 is a lower aliphatic hydrocarbon radical.

16. Process according to Claim 1, characterised in that a starting 17-oxo compound is selected so as to pro-duce a compound selected from a group which comprises the following compounds: 18,18-difluoro-androst-5-ene-3.beta.,17.beta.-diol and its diacetate; 18,18-difluoro-17.beta.-hydroxy-oestr-4-en-3-one and its acetate; 18,18-difluoro-17.beta.-hydroxy-androst-4-en-3-one and its acetate; 3-ethoxy-18,18-difluoro-17.alpha.-methyl-androsta-3,5-dien-17.beta.-ol; 18,18-difluoro-17.beta.-hydroxy-17.alpha.-methyl-androst-4-en-3-one; 18,18-difluoro-17.beta.-hydroxy-17.alpha.-methyl-androsta-1,4-dien-3-one, as well as 18,18-difluoro-3-methoxyoestra-1,3,5-(10)-trien-17.beta.-ol and its acetate.

17. Process according to claim 1 characterised in that a starting 17-oxo compound is selected so as to produce 18,18-difluoro-17.beta.-hydroxy-19-nor-17.alpha.-pregn-4-en-20-yn-3-one.

18. Process according to either of Claim 1 and 9, characterised in that a starting 17-oxo compound is selec-ted so as to produce 17.alpha.-ethynyl-18,18-difluoro-3-methoxy oestra-1,3,5(10)-trien-17.beta.-ol.

19. A 18,18-difluoro compound of the general formula (Ia) wherein R3 denotes a hydrogen atom or a lower alkanoyl group and R4 denotes a hydrogen atom or a lower aliphatic hydro-carbon radical, and St represents a radical of the partial formula , , or (St1) (St2) (St'2) (St3) wherein R5 denotes the oxo group or a hydrogen atom conjoint-ly with an esterified or free hydroxyl group, or denotes two hydrogen atoms, R6 denotes a hydrogen atom or a lower alkyl group, R7 denotes a hydrogen atom or the methyl group, and R denotes a hydrogen atom or the methyl group, it being possible for an additional double bond to be present in compounds of the partial formula St1 in which R is the methyl group, - 27 _ whenever prepared by a process as claimed in Claim 1 or by an obvious chemical equvalent thereof.

20. 18,18-difluoro-17.beta.-hydroxy-19-nor-17.alpha.-pregn-4-en-20-yn-3-one, whenever prepared by a process as claimed in Claim 17 or by an obvious chemical equivalent thereof.