13-epi-steroids and process for the preparation thereof

The present invention is directed to 13-epi-steroids and to a process for the preparation thereof. The subject matter of this specification is divided from Israel specification 72085 filed 13.6.84.

In Israel Specification 72085 there is described and claimed a compound of the general formula

<img file="IL81818A_D0001.tif" />

R and R , which may be the same or different, each represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or

R and R¹¹, together with the nitrogen atom to which they are attached, represent or a 6-membered heterocyclic ring selected from pyrrolidino, piperidino, piperazlno morpholino, oxazolidino, thiazolidino and thiadiazolidino, or

OR^I in which R^ represents a methyl, ethyl, propyl, isopropyl ,methoxyphenyl, allyl or -dimethyl ami noethyl . group,

R represents a hydrogen atom, a methyl group or an ethyl group,

R represents a group of the general formula ־(^CH2^n“^CH3 ⁱⁿwhich n represents 0 or an Integer from 1 to 5, a group of the general formula -(CH₂)_n-CH₂־OR^IV or.

-(CHgJn-CHg-SR^ in which n represents 0 or an integer from 1 to 4, and rI represents an alkyl or alkanoyl radical each having from 1 to 4 carbon atoms, a group of the general formula -CH=CH-(CH₂)_n^RV in which jn represents an integer from 1 to 4, and

R^V represents a hydrogen atom or an alkyl or alkanoyl radical each having from 1 to 4 carbon atoms, a group of the general formula -C C-X in which

X represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms or a halogen atom, a group of the general formula -(CH₂)_n־CH₂CN in which n represents 0 or an Integer from 1 to 3, or a group of the formula -If-CHgY in which

־

Y represents a hydrogen atom or a group of the general formula OR in which R has the meaning given above, R⁴represents a hydroxy group or an alkoxy or alkanoyloxy radical each having from 1 to 4 carbon atoms or

R³ and R⁴, together with the carbon atom to which they are attached, represent a group of the formula

<img file="IL81818A_D0002.tif" />

and R is in the a-configuration and

R is in the ^-configuration or

R is in the S-configuration and

R⁴ is in the a-configuration with respect to the steroid structure, and _d5

K represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms and being in the a-_Or B-configuration, and acid addition salts thereof.

These compounds have a strong affinity for the gestagen receptor without themselves having gestagenic acitivty. They are competitive antagonists of progesterone (antigestagens) and are suitable for inducing abortions since they expel from the receptor the progesterone necessary to maintain pregnancy. The compounds are therefore valuable and interesting with regard to their use for postcoital (p.c.) fertility control.

The present invention provides a 13-epi-steroid of the general formula III

<img file="IL81818A_D0003.tif" />

In which

R^ represents

R¹

a) a group of the general formula in which

X^II rI and H, which may be the same or different, each represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or rI and rH, together with the nitrogen atom to which they are attached, represent or a 6-memered heterocyclic ring selected from pyrrolidino, piperidino, piperazine morpholino, oxazolidino, thiazolidino and thiadiazolidino, or

b) 0R^״I in which rIH represents a methyl, ethyl, propyl, isopropyl, methoxyphenyl allyl or β-dimethyl-aminoethyl group, 2

R represents a hydrogen atom, a methyl group or an ethyl group, c

R represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms and being in the a or β position.

Ζ represents an ethylene, a 2,2-dimethylpropylene or an ether ketone protecting group, or an N-oxide or acid addition salt of such a compound in which R represents a group of the general formula

<img file="IL81818A_D0004.tif" />

The present invention also provides a process for the preparation of a compound which comprises irradiating a compound of the general formula II

<img file="IL81818A_D0005.tif" />

2 5 in which R , R , R and Z have the meanings given above, or an acid addition salt of such a compound in which R^ represents a group of the formula

<img file="IL81818A_D0006.tif" />

with UV light.

The novel compounds of the present specification are useful in the preparation of the compounds of Israel specification 72085.

Thus a 13a-alkylgonane of the general formula I or N-oxide or acid addition salt thereof as claimed in said specification may be prepared by irradiating a compound of the general formula

<img file="IL81818A_D0007.tif" />

2 5 in which R , R and R have the meanings given above and Z represents an ethylene or 2,2-dimethylpropylene group or other ketone protecting group, or an N-oxide or acid addition salt thereof, with ultraviolet light, and converting the resulting

13-epi-steroid of the general formula

<img file="IL81818A_D0008.tif" />

5 in which R , R , R and Z have the meanings given above, or an N-oxide or acid addition salt thereof into a compound of the general formula I, for example by a method known per se by nucleophilic addition to the 17-ketone group, cleavage of the 3-ketal protection and the splitting off of water from the 4,5-position.

= 8 By irradiation with ultraviolet light, a Up-a~lkyl steroid of the general formula ״ _{i־ converted}. _־i־׳od yield, into the 13-epi-st־r״id (13a-alk_yl steroid) of the general formula III.

The prising .

סו good yield of the conversion product is surAlthough it has long been known that '17-0x0 steroids of the normal series can be converted by _uvirradiation into 13-epi-steroids (A. Butenandt et al ־־r. Deutsch. Them. c־s. 71, !30₉₄₁₁,₎ ־₎, _mixturesth־ starting material and the epimerrsed compound were always obtained, the irradiation times were several Hours and the yields ״ere extraordinary l_o״. _Thesearch for an alternative chemical me־״־ of obtaining the 13-epi series is therefore still going _on, _{as no}״ recent work by _Barto״ ״ j._c._s. _{PerUn I׳} shows. _Thi_s alternative is, however, thought to 20 be unsuitable for the m״־_{ufacture of compo״n(Js} θ_£general formula _{r Be} conditions, the irradiation of expounds of the general formula II (or their N-oxides or salts) is considerably more successful than in the series of 11-unsubstituted 17-oxo steroids: the average irradiation times are only from 10 to 30 minutes and the yields of

13-epi-steroid may be from 60 to 80 %. if desired, the irradiation products may be reacted further without chromatographic purification. Optimum results are believed to depend on a suitable choice of solvent, the concentration of the substrate to be irradiated, and exact adherence to the period of irradiation. These parameters must be ascertained individually for each substrate.

The irradiation may be carried out with the full light of a Hg-high pressure lamp in a quartz glass ו apparatus. The temperature of the reaction solution may be, for example, approximately 25°C and the concentration of the solution preferably from 0.1 to 1.0 % by weight. Tetrahydrofuran and dioxan are preferably used as solvents, but it is also possible to 20 use non-polar aprotic solvents, such, for example, as hexane, cyclohexane, benzene, toluene, and mixtures thereof. The period of irradiation is advantageously from 10 to 50 minutes.

A 13-epi-steroid of the general formula III or 25 N-oxide or salt.thereof may then be converted into a compound of the general formula I or N-oxide or salt

- סו thereof for example according to customary processes as described above, for example by nucleophilic addition to the 17-ketone, de-protection of the 3-ketone group and splitting off of water at the 4,5-position, and including, if desired, conversion of a radical represented by R³ into another such radical and/or of a radical represented by R⁴ into another such radical, at any suitable stage in the process.

Thus, for example, the process may include one or more of the following steps as appropriate:

(i) introduction of a group represented by R³ of the general formula ־(CHg)_nCH₃ in which n represents 0 or an integer from 1 to 4 by an alkali metal-alkyl compound, (ii) introduction of a group represented by R³ of the general formula -C=CX in which X represents a hydrogen or halogen atom or an alkyl radical having from 1 to 4 carbon atoms, by means of a compound of the general formula MC=CX in which X has the meaning given above and M represents an alkali metal or by means of an alkali metal and a compound of the general formula HX=CX in which X has the meaning given above, (iii) hydration of a triple bond in a group of the general formula

-CSCH represented by R³ to form a group of the group of the general formula C0CH₃, (וv) introduction of a group represented by R³ of the general formula -C=C(CH₂)_n OR in which R represents a hydroxyprotecting group and n represents an integer from 1 to 4, by means of a compound of the general formula MC=C(CH₂)_nOR ח ו which R and n have the meanings given above and M represents an alkali metal, and hydrogenating the resulting compound to form the corresponding hydroxyalkenyl or hydroxyalkyl radical of the general formula -CH=CH-(CH₂)_nOH or -CH₂CH₂(CH₂)_nOH,

ך (v) oxidising a compound in which R represents a 3-hydroxypropyl 4 group and R represents a hydroxy group to form, with the carbon atom to which they are attached, a group of the formula

<img file="IL81818A_D0009.tif" />

(Vi) introducing a CHgCN group represented by R³ via formation of a spiro compound and splitting the spiro compound with HCN, (vii) introducing a CHgOH or COCHgOH group represented by R³ by converting the 17-ketone to the corresponding 17-halo-17-alkoxycarbonyl compound, converting the halo group to an alkoxy group and reducing the 17-alkoxycarbonyl group to a CHgOH group, and, if desired, converting the 17-alkoxy group to a 17-hydroxy group and also, if desired, converting the CH^OH group to a COCHgOH group, (viii) converting a hydroxy group represented by R⁴ into an alkoxy or alkanoyloxy radical and/or converting a hydroxy group in a radical represented by Rg into an alkoxy or alkanoyloxy radical, (ix) converting a compound having a group represented by R¹ into an acid addition salt thereof.

Nucleophilic addition at the C-17 position generally results in formation of both possible isomers; these are, however, readily separable by chromatography or fractional crystallisation. In many cases, both isomers are pharmacologically active, even though there may be differences in their strengths of action.

The nucleophilic addition of, for example, acetylene (ethylene) or propyne may be carried out using an agent that yields the radical -C=CH or -CHC-CH₃. Such agents are, for example, alkali metal acetylides, such as, for example, potassium and lithium acetylide or methyl acetyl ide.

The organometallic compound may also be formed in situ and reacted with the.17-ketone of the general formula III. For example, acetylene and an alkali metal, especially potassium, sodium or.lithium, may be made to act on the 17-ketone in a suitable solvent in /2

- the presence of an alcohol or in the presence of ammonia .

or 1?-cyanoalkyl

To introduce a 17-alkyl/group, an alkali metal °^r »״tyl-lithium, ־r ־Ik״־ 5 may be used for reaction with the 17-ketone. Suitable solvents are, especially, dialkyl ethers, tetrahydrofuran, dioxan, benzene and toluene.

A 17־ethynyl-17־hydroxy compound'may be hydrated in alcoholic solution with mercury salt catalysis to 10 form a 17-acetyl-17-hydroxy compound (chem. Ber. 111 (1978) 3086 - 3093).

A 3-hydroxypropy1 or 3-hydroxypropenyl radical may be introduced into the 17-position by reacting the corresponding 17-ketone with a metallated derivative of 15 propargyl alcohol, for example with 1-lithium 3-tetrahydropyran-2¹-yloxyprop-1-yneto form the 17-(3-hydroxyrop-1-_ynyl)-i7-hydroxy compound which is then hydrogenated to form the l7-(3־hydroxyropyl or ³־hydroxypropenyl)-17-hydroxy compound. The hydrogena20 tion must be carried out under conditions that ensure that only the C-C triple bond is affected and that the tetrasubstituted 9d0)-double bond is not saturated. This is possible, for example, if the hydrogenation is carried out at room temperature and normal pressure in 25 a solvent such, for example, as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate with the addition of a noble metal catalyst, such, for example, as platinum or palladium.

A compound with Z-configured double bond in the hydroxypropenyl group may be formed, for example, by 5 hydrogenating the acetylenic triple bond with a deactivated noble metal catalyst (J. Fried, j.a. Edwards: Organic Reactions in Steroid Chemistry, van Nostrand Reinhold Company 1972, page 134, and H.O. House: Modern Synthetic Reactions 1972, page 19).

Suitable deactivated noble metal catalysts are, for example, 10 % palladium on barium sulphate in the presence of an amine or 5 % palladium on calcium carbonate with the addition of lead(II) acetate. The hydrogenation may be discontinued after the absorption 15 of one equivalent of hydrogen.

A compound with E-configured double bond in the hydroxypropenyl group may be formed, for example, by reducing the acetylenic triple bond in a manner known se. a whole series of methods for converting 20 alkynes into trans-olefins are described in the literature, for example reduction with sodium in liquid ammonia (J. Am. Chem. Soc. 63 (1941).216), with sodium amide in liquid ammonia (J. Chem. Soc. 1955, 3558), with lithium in low-molecular weight amines (J. Am.

Chem. Soc. 77 (1955) 3378), with boranes (J. Am. Chem. Soc. 93 (1971) 3395 and 94 (1971) 6560), with diiso butylaluminium hydride ane methyllithium (J. Am. Chen. Soc. 89 (1967) 5085) and especially with lithium aluminium hydride/alcoholate (J. Am. Chem. Soc. 89 (1967) 4245). A further possibility is the reduction of the triple bond with chromium(II) sulphate in the presence of water or dimethyl formamide in weakly acidic medium (J. Am. Chem. So4358 (1964) 86 .־) and generally reduction by the action of transition metal compounds with a change in the oxidation stage.

⁰ If an end product in which CR³R⁴ represents

<img file="IL81818A_D0010.tif" />

on

If R¹ then for

1־ desired, then a ״-(J-hydroxypropyD-n-hydroxy compound may, for example, be oxidised in a manner know״ ־־. The oxidation conditions generally depend the nature of the substituent R¹ in formula I. represents, for example, _a dialkylamino group, chromic acid reagents are generally unsuitable oxidation since they attack primarily the dialkylamino group. In such cases an oxidation agent such, for example, as silver carbonate/Celite (Fetizon reagent; M. Fetizon and «. _Ooliier, _Compt. _rend. _(W8J°r Platinum/oxygen (H. Muxfeldt et al., Angewandte Chemie, I״t. Bd. 1 (,962) 157) may be used. ״, _{on the}

6ו other hand, R¹ represents an alkoxy Radical, it is also possible to use an oxidisin, ־־ent such, for exampu, “ Jones reagent, chromic acid-p_yridine, pyridinium dichromate or pyridinium chlorochromate.

A 1J-cyanomethyl side chain may be introduced, for ־xanple, in a manner known per se from the 17-ketone of the general formula III, for example via the 17-spiroepoxide and bv cl««!™ na oy cleaving the spiroepoxide with HCN according to z. chem. is (1978) 259 . 260.

The introduction of a 17-hydroxyaoety1 ־!de chain ”ay also be carried out according to methods known ger ־־, for example according to the method described in j. Org. Chem. 47 (1982), 2993 -2995־.

₄ If desired, a f_ree hydroxy group represented by * i״ the 17-position may be esterified or etherified, for example, in a manner known per se.

free hydroxy or mercapto group in the represented by R³ may, _{if desired}, _be

Splitting off of water, with the 4(5)־double bond, and simultaneous ketal group in the 3-position (and protecting groups present that can acid) may be effected with acid or exchanger.

Similarly, a radical or etherified / esterified.

formation of the cleavage of the removal of any other be split off with an acidic ion

־ ¹⁷ ־

The preparation of the compounds of the present invention are described in Examples la, 2a, 3a, 4a and 5f hereinafter, the remaining sections of said examples illustrating procedures utilizing the present compounds, however not constituting part of the present invention.

Examples

Example 1

a) A solution of 2.0 g of 11β-(4-cimethylaminophenyl)-

3,3-(2,2-dimethylpropane-1,3-dioxy)-5a-hydroxy-9(10)oestren-17-one (m.p. 143 -145°C) in 300 ml of absolute tetrahydrofuran (THF) is irradiated for 16 minutes at 25°C with a Hg-high pressure lamp (Philips HPK 125, immersion lamp, quartz glass reactor). The solvent is then distilled • vacuo and the residue is chromatographed over aluminium oxide (Merck, neutral, stage III) with hexane/ ethyl acetate. 1.46 g of 11β-(4-dimethylaminophenyl)-3,3(2,2-dimethy!propane-1,3-dioxy)-5a־hydroxy-13a-methyl10)9־)gonen-17-one are obtained in the form of a colourless oil.

b) At 5°C, absolute THF (248 ml) is saturated with acetylene by introducing the latter over a period of 30 minutes. 51 ml of a 15 % solution of n-butyllithium in hexane are then slowly added dropwise and the whole is stirred for a further 15. minutes while cooling with icewater. A solution of 2.7 g of 11β-(4-dimethylaminophenyl)-

3,3-(2,2-dimethylpropane-l,3-dioxy)-5a-hydroxy-13a-methyl-

9-gonen-17-one in 40 ml of absolute THF is then added dropwise over a period of 15 minutes to the suspension of the lithium acetylide and stirring is carried out for a further 2 hours at room temperature. For working up, the whole is poured into ice-water and extracted with ethyl acetate. The resulting crude product (2.85 g) is used in the following stage without being further purified.

c) 2.3 9 of the crude product obtained under b) are suspended in 29 ״!. _of 70 , aqueous _{acetic acid} stirred for 3 hours at 50’C. After cooling, the suspension Is diluted with approximately 700 ml of water and adjusted 5 to a pH of 10.5 by adding concentrated aqueous N_3״ solutlon. After extracting with ethyl acetate, an oily mixture of isomers 1־ obtained that is separated by column chromatography over sill־־ gel with hexane/ethyl acetate. There are obtained in the order of elution:

’ ’. 530 mg of 11,-(&lt;-dim־thyl־ml־״ph״־yl)-1₇־-_־thy״yl17«-hydroxy-13־-methyl-4,9-gonadien-3-־ne having a melting point of 120 - 123C (ethyl acetate/dllsopropyl ether) and

2. 1-33 g of ¹ 4)־5י-dimethylaminophenyl)-17s-ethynyli ¹?«־hydroxy-!3־-m־thyl-4,9-go״adi3-״־-o״e having a melting point of 201 - 204«c (ethyl acetate!. Analogously to b! and c ) , there are obtained using methylacetylene instead of acetylene:

¹ .יH-(4-dlmethylaminophenyl)-1It-hydroxy-l3»-methyl- ¹ ^®־propynyl-,, g-gonadien-3-one in the form of an oil.

²- ״B-(4-dimethylamlnophenyl)-₁₇a-hydroxy-13_o-methyl'”־Pr־pynyl-4,9-g־_nad₁en-3-one in the form of _anoil.

After the addition of 0.37 ml of concentrated sulphuric acid, a suspension of 1.02 g of mercury oxide , - 20 (HgO, red) in 20 ml of water is stirred for 30 minutes at 60’C. 9 ml of this mercury salt solution are added to a solution of 3.25 g of 1 וβ-(4-dimethylaminophenyl)-17β^ethynyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one in 32 ml of glacial acetic acid. The whole is then stirred for hours at 60°C. For working up, the cooled reaction solution is poured into ice-water, adjusted to a pH of 1,0.5 by adding concentrated aqueous NH^ solution and extracted with ethyl acetate. The resulting oily crude product is crystallised from methylene chloride/diisopropyl ether. 2.37 g of 11β-(4-dimethylaminophenyl)-7וa־hydroxy13a-methyl-l8,19-dinor-4,9-pregnadiene-3,20-dione having a melting point of 224 - 225°C are obtained.

e) A suspension of 2.3 g of 11β-(4-dimethylaminophenyl)15 17a-hydroxy-13a-methyl-18,19-dinor-4,9-pregnadiene-3,20- dione in 58 ml of toluene is stirred for 20 hours at 25°C after the addition of 11.6 ml of acetic anhydride and 5.8 g of 4-dimethylaminopyridine. The suspension is then poured into saturated NaHCO₃ solution and extracted with ethyl acetate. The crude product is chromatographed over 200 g of silica gel with hexane/ethyl acetate. After crystalUsing the main fraction from hexane/ethyl acetate, 1.71 _gof 17a-acetoxy-11β-(4-dimethylaminophenyl)-13a-methyl1θ־15׳dinor4,9־-pregnadiene-3,20-cione having a melting point of 194 - 195°C are obtained.

_

Example 2

a) ' A solution of 1.8 g of 11β-(4-diethylaminophenyl)3'32,2)־-dimethylpropane-l,3-dioxy)-5a-hydroxy-9-oestren17-one (m.p. 223 - 226°C) in 300 ml of THF are irradiated for 26 minutes under the conditions of Example 1 a).

After chromatography of the crude product, 1.58 g of 110(4-diethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy) 5a-hydroxy-13a-methyl-9-gon_en-l7-one are obtained in the form of a colourless oil,

b) At O’C, the organo-lithium compound 1, prepared from 3.94 g of 3-tetrahydropyran-2'.yloxy-1-propyne in 85 ml of absolute THF and 23.1 ml of a 15 1 solution of n-b״tyllithium In hexane. A solution of 3.53 g of the product described under 2 al in 71 ml of absolute ΤΗΓ is then added dropwise and the whole is stirred for 4 hours at room temperature. The reaction solution is afterwards poured into ice-water and extracted with ethyl acetate. The crude product 13.85 g) of 114)-־-diethylaminophenyl).

3,3-(2,2-dimethylpropane-1,3-dioxy)-13»-methyl-173)-־- *^tetr^ahydr־pyr־n-2-yloxy)-1-propynyll-9-go״e״e-5a, 1 7fi-dio! ana 114- (4-diethylaminophenyl) -3,3- (2 ,2-d'imethylprooaneV3־dloxy)-13a-methyl-170-[3-( tetrahydropyran-2-yloxy)-ו Ptopynyl)-9-gonene-5a,17a-diol is used for hydrogenation without being further purified.

c) After the addition of 400 mg of 10 % palladium/ carbon, 3.85 g of the crude product obtained under 2 b) are hydrogenated in 95 ml of ethanol at room temperature and normal pressure. After 191 ml of hydrogen have been taken up, the catalyst is filtered off and concentration 5 is carried out.

d) The crude hydrogenation product (3.85 g) obtained under 2 c) is stirred in 30 ml of 70 % acetic acid for hours at 60°C. After cooling, working-up is carried out as under 1 c) and the resulting mixture of isomers is chromatographed. There are obtained in the order of elution:

1. 410 mg of 11β-(4-diethylaminophenyl)-17a-(3-hydroxypropyl)-17B-hydroxy-13a-methyl-4,9-gonadien-3-one in the form of a yellowish oil.

UV (methanol): e, = 19080, _ε = 19110.

v v כ u ע

2. 1.39 g of 11¢-(4-diethylaminophenyl)-17β-(3-hydroxypropyl)-17a-hydroxy-13a-methyl-4,9-gonadien-3-one in the form of a solid foam.

Analogously to b) to d), there are obtained when using 11β-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-

1,3-dioxy)-5a-hydroxy-13a-methyl-9-gonen-17-one as starting material:

1) ¹י^β־⁴)־dimethylaminophenyl)-l7B-hydroxy-17a-(3-hydroxyPropyl)-13a-methyl-4,9-gonadien-3-one in the form of 25 an oil.

2.) 11β-(4-dimethylaminophenyl)-17a-hydroxy-17β-(3-hydroxy23 ' ethynyl-110- (4-methoxyphenyl) -1 3a־meth-.-l-9־gonene5־_tt7 1 _׳adiol׳in the form of a solid foam.

־> A solution of 3.28 g of 3,3-(2,2-dlmethylpropa-־״

3, י-di־xy)H7.-־thynyl-11fl-14-methoxyphenyl)-13־-m־thyl-95 9170,־5-־״־״־-diol in 33 ml of 70 » agueous acetic acid is stirred for 30 minutes at 60c. After cooling, the solution is poured into !־־-water and extracted 1״th ׳»ethyl־״־ chloride and the Mecq extracts are ״ashed with saturated N.HCO, solution and concentrated. Crystallise10 tion of the crude product from ethyl acetate yl1־_{ds 2}.0g of 17fl-־thynyl-17«-h_ydroxy-11.-(4-m־thoxyph־nyl)-,₃a׳»ethyl-4 ,9-gonadien-3-one having ־ _B._{ltlng p01nt 0£} ,_־־ . 187°C.

.25

Example 4 minutes' irradiation of 1.8« , of 1,.-(4-dimethyl1״־noph־nyl₎,3-₍2,2-dlm־thylpr־p־_n3,,.־._aioxyl._5־._hydroxy. 18-m־thyl-_S-o־stre17-״-o280 ״1 ־״ ml of THE under the oondltlons of Example 1 a, results in 1._3S , _0£dlmethylaminophenyl).₃,₃-(2,2-dimethylpropane-1,3-dioxy). l3»-־thyl-₅־-hydr־xy-9-_gone17-״-one in th. form of a foam.

methylpropane־1,3־dioxy)-13 one are lithium

8.1 g of 11.-(4־dimethylaminophenyl)-3,3-(2,2-dla-־ethyl5־a-hydroxy-9־gonen-1 7re reacted under the conditions of Example 1 _b) ״!th acetylide and the resulting crude product is ־leaved 1״th.acetic sold under the condition־ of Example ־ ־־״. .׳־ יh-־t₉־r־phy _{and crystallisation fr0B}^y ־־־t־t־/d_ils־_{propyl ather}. ' a׳ninophenyl)-1_7fl-_p1.H , ⁶ «־dimethyl-״yl) ’⁷־-־‘hy״y1-13־-_eth_yl-״_a._hyddisn^w3*or«A k . J 2 > י gons — ^en צ one having a meltin« ~ , ־ obtained ׳<

50.4 ⁰ (Curl (CHC1₃, _c = 0.505).

, c)

By hydration, catalysed w״h ״״ to Example 1 d) and h ⁷ *^״t' ^a^a10־ • ¹ 0) and subsequent- ״״,־a. י to Example 1 _e) th ^analo90us θ’׳ ^thera are obtained from 1 _{3o f} “l״othyl־ml״_ophenyl). •3 9 Of 115-(48 ^ethyⁿyl-13a-ethvl-1 7״ >, ⁴־9׳gonadien-3-one, after h ־״hydroxyer chromatographic ourtr

720 mg of l_7a-_arp, ^purifnation,

Pregnadiene-3 ₇n_ju °t a solid foam ״* ^־״° ׳ ^{the form} (־I²⁵

D * 290.8° (CHC1₃, c ₀.5₁₅ ־₎ gous

Example 5 ” ^{A suspe}״slon of 29.3 _{g 0£ 3} :----1 3 ׳~dloxy)-5 (, Q, _Q ,,,, ' ^ln1ethylpropane^,⁰־'¹*’*^,5״”-one ,nd ״ a °0 his-dimethylamino-tert -butox v 9 of ־ot. butoxymethane is stirred _M^ar9°״ ^£or ”I־־!״״ at 160-c Aft. — - triturated _{K״h a p} “ ‘°°⁹^״' “θ ——״⁵⁰יה:::: ב— ethyl _acetat⁰“ _״ ._־“θ ¹⁵ 1»״׳&lt;»״in this manner דל e.

'* ^dira*^thy^laminomethyiene-3 5-0 ⁹ ־ ' ל^of־^6ו Ιύβ; ί, ' ' ־^dlmethylpropane-i 5 ;9(l1)-oestra^hn&lt;־־?1־@_{He havi} ׳ י' °^Xy)־ ' ^{§he havi}9 a siting po_{int of}

סו

208 - 211 °C are

b) 85 nil of ether are added obtained .

a 5 » solution of methyllithium in diethyl dropwise while cooling wl-.h ice-water to a solution of 14.4 g of 16-dlm־thylaminometh_y1e״e-3,3(2,2-dim־th_ylpr־pa1,3-־״-dl־x_y)-5(10),9(״|-o־stradien’7-־״־ in 220 ml of toluene, when the addition 1־ complete, the whole is stirred for 15 minutes at .5 to .Wc, excess reagent is decomposed by the careful addition of approxlreaction solution is then -- ice-water and extracted mately 20 ml of water and the poured into approximately 3 1 of ice-water and extracted 1״th methylene chloride. The crude product is chromatographed over neutral aluminium oxide with h־x־n־/־th_yl acetate. After crystallisation of the main fraction from athyl acetate, 13.0 g Of 3,3-(2,2-dlmethylpropa1,3-־״dioxy)-16(_£)-־th_ylld״־e-5(10),9(11)-oestradien-17-0״e having a melting point of 121 - 123°c are obtained.

4.3 1״ of 30 , hydrogen peroxide ere added dropwise while cooling with !־־-water to' a solution of 9.4 g of 3,3-(2,2-dlm־th_ylpr־p־_ne-1, ⁹i11)-oestradien-17־one in 43 ml of 0-34 ml of hexachloroacetone and 0.01 then the whole is stirred for 16 hour methylene chloride, ml of pyridine and s at 25°C. For working up, the reaction solution is diluted aiiuted with approximately

100 ml of methylene chloride and washed ir _B״e wasnea m succession. with

0־

5. Na₂S₂O₃ solution and water; the methylene chloride phase is dried over Na₂SO₄ and concentrated. The resulting 5,10-epoxide mixture is chromatographed over Al^, neutral, stage III, with hexane/ethyl acetate. 4.7 g of

3,3-(2,2-dimethylpropane-1,3-dioxy)-5a,10a-epoxy-16(e)ethyliden-9(11)-oestren-17-one having a melting point of 141° - 39יC (ethyl acetate/diisopropyl ether) are obtained.

d) After the addition of 930 mg of palladium/carbon (10 %), a solution of 8.2 g of 3,3-(2,2-dimethylpropane- ׳ י סי-dioxy )-5a, 10a-epoxy-16( E)-ethyliden—9 (11 )-oestren-

17-one in 400 ml of ethanol-is hydrogenated at room temperature and normal pressure. After 510 ml of hydrogen have been taken up, the catalyst is filtered off and concentration is carried out in'vacuo. 7.7 g _Of ₃__3׳ י s (2,2-dimethylpropane-1,3-dioxy)-5a,10־-epoxy-16p-ethyl9¢11)-oestren-17-one are obtained in the font of a colourless oil.

e) An organo-magnesium compound is prepared from 1.4 _gof magnesium, 0.05 ml of methyl iodide and 17.9 g of

4-bromo-N,N-dimethylaniline in 150 ml of.absolute THF.

After the addition of 344 g of CuCl, the whole is stirred . for 15 minutes at 0°C and a solution of 7.7 g of the product obtained under d) in 70 ml of absolute THF is then added dropwise. Afterwards, the whole is stirred for 3.5 hours at room temperature. For working up, the reaction

7^ti0^{i־ poured}^lnt° ^a ««״ Of >״״־-״ _{and NB}-- -ס extracted ״!״ _e״yl

P y of the ״Ude product over aluminium _oxldehexane/ethyl acetate and crystal!!״־, .

^ryStallisation of the main ״־on from diisopropy! ether/ethy! acetate, ₆._5gof ^^S~⁽'~^din1ethy^laminoP^he״y¹)-32,2)-3׳-dimethylProPane-1^f3־xy)-1־־-eth־5.״.h_ydrox_y._S(10)._oestren.₁₇._one .melting point of 180 - 181’r _a . ⁹ ו»^ו C are obtained.

f)

סו

לי

A solution of 4.0 _q of j . ⁹ °^{f the} P^rodu^t obtained under ^ln 600 ml of dioxan is _irradl. . י . eradiated under the conditions of Example 1 al if♦.״ ^ns p a). After crystallisation of _the ״״״, irradiation product from diisopropy! _eth־r , ,, ' «-aim־t_hy!a_{minoph υ}. ‘ . ⁹ °^f ”⁸־ ifi« ^J (2־²׳^d1methylpropa״e-13_׳-dioxv) ³ θ' ¹³² ׳»’ ־C are obtained.

e)