DE2531145C2 - Process for the preparation of 11beta-hydroxy-18-alkyl-steroids of the estran series - Google Patents

Description

HO CH ₃

ι in which Ri = H ₂ , H (OAcetyl) or Äthylendioxy and R ₂ = Äthylendioxy, * H (/ SOAcetyI) or («-Alkyl I -4 C) (, / SOAcetyl) means, converted into cyclohexane with 0.5 up to 1 mole of iodine and 1.5 to 3 moles of lead tetraacetate per mole of iodine, in the presence of azoisobutyrodinitrile, which protects the 11/7 hydroxyl group of the 1 l / f-hydroxy-13-iodomethylgonane compound obtained by forming the trimethylsilyl ether and the product obtained is reacted with an alkyllithium compound having 1 to 4 carbon atoms, the resulting compound is treated with water and the 18-carbaldehyde compound obtained is reduced by converting the carbonyl group into the hydrazone or semicaibazone and decomposition under alkaline conditions or reacting with a triarylalkylidene phosphorane and the obtained 18-Alkenyl compound reduced with hydrogen in the presence of a noble metal catalyst to the corresponding 18-Alkyiverbverbindungen.

The invention relates to a new process for the preparation of 1 \ fl- hydroxy-18-alkyl-estran compounds.

Y, 18-alkyl-estran compounds are pharmacologically important 19-nor-steroids. An example of such a compound is norgestrel (17it-ethynyl-7 ^ -hydroxy-18-methyl- / i ⁴ -estren-3-one) which is used as an oral progestative agent and, among other things, as a progestative component in contraceptive. Many 18-alkyl-estran compounds are described in the literature which have different hormonomimetic properties. It turns out that these compounds are generally more active than the corresponding 13-methyl compounds.

The natural steroid hormones have a methyl group in the 13-position. This methyl group is only exceptionally substituted, e.g. B. in an aldosterone. Most synthetic 19-nor-steroids that are therapeutic Have found application are manufactured on an industrial scale, starting from natural Steroids, modification and / or elimination of the substituents present in the steroid skeleton and / or Introduction of substituents into the steroid molecule and / or introduction or saturation of double bonds. The 13-methyl group is not attacked in these reactions. So far the 18-alkyl-estran connections have been used obtained by total synthesis, the steroid skeleton being built up from smaller molecules and the 18-alkyl group has been incorporated by appropriate selection of the starting materials. The total synthesis is a long and arduous process, especially because of the large number of asymmetric carbon atoms present in the steroid skeleton. Admittedly, many synthesis problems were caused by a suitable selection of the starting substances and resolved by the discovery of slereospecific reactions, but there are still many Separations of isomers and purification steps are required, as a result of which the yields are low and the costs are low become relatively high. That can partly be a reason why 18-alkyl-estran compounds despite their promising properties and strong activities in the literature for such Connections are given, in fact have found little application.

The new process for the preparation of 1 l ^ -Hydroxy-18-alkyl-estranverbindungen consists in that one

(a) a 1 \ ß- hydroxy-13-methylgonane compound is used as the starting compound,

(b) this steroid reacts with an acyl hypoiodide and

bO (c) converts the 1! ^ - hydroxy-13-iodomethylgonane compound obtained in this way after protecting the 11 ^ -hydroxy group with an alkali alkyl compound or with dimethylformamide in the presence of an alkali alkyl compound and then treated with a Proionendonalor, whereupon in the latter case the obtained 18-carbaldehyde group reduced to the 18-methyl compound or with a trialkyl or triaryl alkylidene phosphorane (Wittig reagent) is reacted and then the 18-alkenyl compound thus obtained

b5 is reduced to the corresponding 18-alkyl compound.

In this way, 1! // - Hydroxy-IS-alkyl-oil-oil compounds can be formed in an elegant and simple manner and with good to excellent yields can be produced without stcreoisomerc problems. These

So far, compounds could only be obtained with the help of the difficult total synthesis.

The advantages of starting with 1 l ^ -hydroxy-13-methyl-gonane compounds are the presence of the 1 \ ß- hydroxy groups, which make it possible to make the 13-methyl group reactive by reacting with an acyl hypoiodite and 11 substituted 18-alkyl ! to make compounds in a simpler way than by total synthesis.

The H ^ -hydroxy-13-methylgonane compounds which can be used as starting substances can contain substituents in other positions on the ring system, such as oxo groups (and preferably functional derivatives thereof) in the 3- and / or 17-position, free, esterified or etherified hydroxyl groups in the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 15- and / or 16-position, the free hydroxyl groups preferably being protected during the process according to the invention, alkyl groups such as methyl or ethyl groups in 1-, 6-, 7-, 9-, Wx- and / or 16-position and / or a saturated or unsaturated alkyl group with 1 to 4 carbon atoms, such as a methyl, ethyl, isopropyl, vinyl , Äihinyl, isopropenyl, propadienyi or butenynyl group in the 17'-position in the vicinity of a free esterified or hydrolyzed hydroxyl group in the 17'-position. Functional derivatives of oxo groups are to be understood as meaning ketalized oxo groups or oxo groups which have been converted into enol derivatives, such as enol ethers or enol esters. Furthermore, the starting substances can also contain double bonds, e.g. B. in 4,5-, 5,6- or 5,10-position.

Preferred starting substances are the 1 i / tf-hydroxy-13-methyl-gonane compounds of the formula:

HO CH ₃ R ₂

in the

Ri = H ₂ , H (OR ₃ ), O or ketalized O;

R ₂ = O, ketalized O, H (OR ₄ ) or (Λ-alkyl) CoOR ₄ ), where the alkyl group contains 1 to 4 carbon atoms and R ₃ and R ₄ each have a hydrogen atom or a protective group, such as an acyl or alkyl group, preferably an acetyl group, and a double bond is present in the 4,5- or 5,6-position.

Examples of such starting substances are:

ll ^ -hydroxy- <4 ⁵ -estren-3,17-dione-3,17-diethylen-ketal,

U / ^ / i-Dihydroxy-zP-ostren-S-on-S-ethylene-ketal - ^ - acetate,

U /? - Hydroxy- ^ ⁴ -estren-17-one-17-äthyleri-ketal,

Δ "-östren-11 / ?, 17 /? - diol-17-acetate,

1 l ^ -Hydroxy-J ⁴ -östren-3,17-dioii, S / y.ll / yDihydroxy ^ oestren ^ onOacetatnä

1 l /? - Hydroxy-zf ⁵ -estren-17-one-17-ethylene-cctal,

Δ ⁵ -estren-1 \ ß _% \ 7 /? - diol-17acetat,

1 \ ß, \ 7 /? - Dihydroxy-17 «-methyl-z / ⁵ -estren-3-one-3-ethylene-ketal-17-acetate

and the corresponding 17 "-ethyl compound.

Known furan compounds without a 1!, Tf -hydroxy group can easily be converted into the starting compounds for the process according to the invention by introducing, for example, a microbiological route of a 11 "-hydroxyl group with the aid of, for example, the microorganism Aspergillus ochraceus, Rhizopus nigricans or Pestalotia royena and subsequent oxidation of the I. ! «- hydroxyl group, for example with chromic acid to the 11-ketone, whereupon the 11-ketone by reduction z. B. with NaBH _{4 is converted} into the H / i-hydroxy estran compound. So 19-nor-testosterone z. B. microbiologically converted into 11 "- hydroxy-19-nor-testosterone and this compound converted with Jones reagent to the corresponding i, | 11,17-diketone (zi ⁴ -östren-3,11,17-trione), whereupon this 3,11,17-triketone after protection of the 3- and 17-oxo groups

Ip pen in the form of a ketal by reduction with NaBH ₄ in the II /? - Hydroxy-zP-estren-3,17-dione-3,17-diketal ^ι 'Α is converted.

The 11 /? - hydroxy group can also be introduced directly by microbiological means, e.g. B. with the '*' Microorganism Curvularia lunata.

ij "The 11 /? - Hydroxy-13-methyl-gonane compounds that can be used as starting substances are initially described in

S ', the first stage of the process according to the invention, reacted with an acyl hypoiodite, a il / i-hydroxy-13-iodo-methylgonane compound being obtained. The Acylhypojodit is preferably the silver, mercury and Bleiacylaten prepared in situ from iodine and an acylate of a heavy metal such as the acetates, propionates and benzoates of the metals of the first, \ second and fourth subgroup of the periodic table 1. B.. A lead tetraacylate, such as lead tetraacetate, is preferably used, which with) od forms a lead diacylate and an acyl hypoiodite. The acyl hypoiodite converts the 11 / y-hydroxy group into the 11 ^ -hypoiodite group, whereupon the I i / y-hydroxy-13-iodomethyl compound is formed by means of an intramolecular conversion.

This step is preferably carried out by the starting substance in one opposite the

Reactants inert solvent dissolves or suspended, z. B. a hydrocarbon such as cyclohexane or methylcyclohexane or a »chlorinated hydrocarbon such as dichloromethane, carbon tetrachloride or hexachlorobutadiene and lead tetraacetate and iodine and, if necessary, a weak alkali, eg. B. calcium carbonate is added and the reaction mixture is heated with stirring. The reaction can be carried out under normal pressure or elevated pressure, and e.g. B at the boiling point of the solvent under reflux. The duration of the reaction depends, among other things, on the temperature and the solvent used. When working with iodine and lead tetraacetate in cyclohexane under reflux, the reaction is generally complete within one hour. The temperature is usually kept between 50 and 150 ° C.
! The rate of reaction can be accelerated by irradiating the reaction mixture with visible and / or ultraviolet light. However, a free radical initiator is preferably used. for this purpose added to the R-jaction mixture. It was found that the addition of, for example, azoisobutyrodinitrile has a very favorable effect on the reaction time. The amount of free radical initiator added is not very critical. Excellent results are obtained with amounts of 0.1 to 0.25 mol per mole of steroid.

To achieve good yield, the amount of iodine in the reaction mixture should be selected such that per MoI steroid at least 0.5 mol \ i are available. Preferably some excess of J2 is used, usually no more than 1.5 moles of J2 per mole of steroid. The amount of lead tetraacylate, expressed in moles, should be at least equal to the amount of |>, but is preferably greater. Usually 1.5 to 3 moles of lead tetraacylate are used per mole of J2.

The duration of the reaction is closely related to the amount of iodine used. If a larger excess If iodine is applied, the reaction time should be shortened in order to avoid the formation of the II /? - hydroxy-13-iodomethyl compound reacts again and via the 1 l / ä'-acyl hypojodite the 1 l / ^ - hydroxy-IS-diiodomethyl compound biidet. The formation of this latter compound would reduce the yields of the desired 1 i / f-hydroxy-13-iodomethyl compound naturally have an unfavorable effect.

In boiling cyclohexane and in the presence of a radical initiator, the reaction time is, if one Amount from 0.5 to 1.0 moles of J? per mole of steroid used, between about 10 and about 30 minutes, and if approximately 1.5 moles of Ji are used per mole of steroid, the reaction is complete in a few minutes expired.

In the case of the ii / f-hydroxy-U-iodomethylgonane compound obtained in the first stage, the 1 l /? -Hydroxy group becomes then temporarily protected. This can be achieved effectively through the formation of an ether. The protection by ester formation is not effective, since an ester group under the conditions of the next reaction step would also react.

Trimethylsilyl ether has proven to be extremely suitable as a protective ether. The etherification will , e.g. B. carried out by reacting the 11 ^ -hydroxysteroids with trimethylchlorosilane in a solvent, such as pyridine and at low temperature.

According to the method according to the invention, the 1 l / ^ ether of the 1 i ^ -hydroxy-13-iodomethyigonan compound is then used reacted with an alkali alkyl compound, or it is reacted with dimethylformamide in the presence an alkali alkyl compound and then treated with a proton donor.

An alkyl-silicon compound is preferably used as the alkyl-alkyl compound. Examples of such Compounds which are preferably used are alkyllithium compounds having 1 to 4 carbon atoms, such as Methyl lithium, ethyl lithium, butyl lithium.

The reaction with the alkyllithium compound is carried out in a solvent under anhydrous conditions at conventional temperatures, e.g. B. carried out in dry ether or dry tetrahydrofuran and under a nitrogen atmosphere. In this way the 1I / J'-ether of the corresponding 1i / i-hydroxy-18-alkyl-estran compound is obtained from the 11 /? -Ether of the 1 \ ß- hydroxy-13-iodomethylgonane compound.

The ether group in 11-position can be removed by hydrolysis, e.g. B. by treatment with hydrochloric acid in Acetone can be removed.

When reacting with dimethylformamide, the same compounds as mentioned above are used as alkali

kylverbindungen applied, z. B. Mcihyllithium or Butyllithium. The reaction will take place at room temperature under anhydrous conditions in an inert solvent, e.g. B. diethyl ether or hexane carried out.

The resulting Dimethylaminoearbinolverbindungen in the form of Lilhiumalkoxids is then with the help of a Proton donor degraded to the 18-carbaldehyde. Water is suitable as a proton donor. It can also a dilute ammonium chloride solution or optionally an organic acid such as Oxalic acid. The decomposition reaction is usually carried out by the reaction mixture of Reaction with dimethylformamide is poured into water, the optionally dissolved ammonium chloride or oxalic acid contains. The 18-carbaldehyde is extracted, e.g. B. with methylene chloride, the extract is evaporated and the residue, if desired, purified, e.g. B. by chromatography.

The H / f-hydroxy-IB-carbaldehyde compound can also exist in the isomeric form as (18a -> · 1 l / f) -carbolactol (the cyclic Hcmiacetal) with which it is in equilibrium.

The 18-carbaldehyde is then reduced to the 18-methyl compound or, if appropriate, first mil; A Wittig reagent is reacted to give an IHA-kenyl compound which is thin to the 18-alkyl compound dung is reduced.

The reduction is günstigerweisc performed by the Wolff-Kishner method, whereby dieCarbonylverbindung in the Hydra / or on Semiearba / on the reverse change ¹ wild, and the hydrazone or semicarbazone mil alkali decomposed. This decomposition is carried out with the aid of potassium hydroxide or with an alkoxide such as sodium ethoxide. The 1 lang-Minlon modification is preferably used, the decomposition being carried out in a high-boiling solvent such as diethyl glycol and the water formed during the reaction being distilled off.

The reaction of the 18-Carhaldchyds carried out with Wittig reagent (a triaryl or

Trialkylalkylidenephosphorane), ζ. B. with triphenylmethylphosphorane or triphenylethylidynphosphorane - the Wittig reagent is made in situ from a trialkyl or triaryl phosphine. z. B. triphenylphosphine and one Alkyl halide, ζ. B. methyl or ethyl bromide with the help of a suitable base such as butyllilhium, ethylmagnesium bromide, Dimethyl Sodiumamide or Dimsyl Sodium - is made in a suitable solvent, such as dimethyl sulfoxide, diethyl ether, dioxane or tetrahydrofuran carried out.

The 18-alkylene compound thus obtained is finally converted into the alkyl estrane compound. This can conveniently be achieved by reduction in a suitable solvent such as tetrahydrofuran or methanol with hydrogen in the presence of a Edelmeuill catalyst, e.g. B. Pd / BaSO ₄ or Adams catalyst (PtOj). preferably and in the presence of a small amount of acetic acid.

The 1 / y-hydroxy-1S-alkyl-estran compounds produced by the process according to the invention are effective Can easily be converted to important known compounds, such as /. B. 17, i-Aihinyl-17 / y-hydioxy-18-me-

Thym ⁴ -estrene-3-one (Norgestrel =) and 1 i-A-ethynyl Methylcn- ^ - ^ / y-hydroxy-IB-methyl-J ^'1 estrene-3-one, both very effective progestational compounds. To produce known compounds that are unsubstituted in the 11-position, the 11 /? - hydroxyl group is oxidized with chromic acid or with the aid of Oppenauer oxidation and the 11-oxo group thus obtained is reduced by the Wolff-Kishncr process, whereupon other desired substituents in the ΐϊ molecule are added methods known per se are introduced, /. H. a 17λ-Αι-hinyl-17 / y-hydroxy group can be introduced into a 17-ketone using the known reaction with Kiiliumucctylid. To produce 11-methylene compounds, the 11 /? - hydroxyl group is also oxidized as indicated above and the 11-oxo group thus obtained is reacted with, for. B. triphenylphosphorylmethylene (Wittig reagent), whereby the 1 1 /? - methylene group is formed (see e.g. ZA-PS 73/9161).

Any ester group that may be present is derived from an organic carboxylic acid with 1 up to 18 carbon atoms. An ether group is, if it is present, for example a methyl ether, ethyl ether, Tetrahydropyranyl ether or trimethylsilyl ether group. A ketal group, if present, is e.g. B. the Ethylene ketal or dimethyl ketal group.

The invention is illustrated in more detail by the following examples.

example 1

a) 19.8 g of lead tetraacetate (washed 3 with cyclohexane) and 3.87 g of] od were suspended in 350 ml of cyclohexane. The mixture was refluxed for 20 min and then cooled to room temperature. Then 9.9 g of II / -hydroxy- // ' ⁱ -estren-3,17-dione-3,17-diethylene ketal and 0.69 g of azoisobutyrodinitrile were added and the mixture was then refluxed for a further 20 minutes. The reaction mixture was filtered through filter aid (Hyflo) and the filtrate was washed with water until neutral. The organic layer was _{dried over Na2SO 4} , filtered and evaporated to dryness in vacuo. Weight of residue: 12.65 g. The residue was taken up in 25 ml of ethanol and left to stand at -20 ° C. overnight. The resulting crystals were filtered off and dried. In this manner, there was obtained 6.21 g of 11 // - hydroxy-18-iodo - // ⁵ -estrene-3,17-dione-3,17-diäthyIenketal, mp 143-144 ⁰ C. ί.

17 acctai, ^ ■ '-estrene-1 l / ^5>, - Similarly, the 11 / ^ were 17 _/ 6'-dihydroxy-zi' ⁱ -estrene-3-one-3-äthylenketal-17 /) ' _/ ? -diol-17 / -acetate, 1 l /? - hydroxy- / J ° -estren-17-one-17-ethylene ketal and 11 />". 17 /? - dihydroxy-17" -methyl- Δ ⁵ -estren-3-one-3-ethylene ketal-17 /? - acetate converted into the corresponding 18-) od compound.

b) 6.2 g of 1 l ^ ^{-hydroxy-18-iodo-5} were zi -estrene-3,17-dione-3,17-diäthylenketal dissolved in 42 ml of dry pyridine, the solution was cooled to 0 ⁰ C and then b ml of trimethylchlorosilane were added within one hour. The reaction mixture was then stirred at 0 ° C. for 2 hours and poured into 0.5 l of ice water. The crystals were filtered off and dried over KOH in vacuo at room temperature. In this way, 6.44 g of 11 /? - Hydroxy-18-iodo-J '-estren ^^ - dione-l 1 _i δ'-trimethylsilyl ether-3.17-diethylene ketal were obtained. Mp. 153-155 ⁰ C.

In a similar manner, the 11 /? -Hydroxy-18-iodine compounds obtained in Example la) were converted into the corresponding 1 l /? - trimethylsilyl ether converted.

c) To 1.15 g (2 mmol) of 11 /? - Hydroxy-18-iodo-I ^ -estren-S.W-dione-S. ^ - diethylene ketal-i ^ -trimethylsilyl ether in

20 ml of dry THF, 5 ml of 2η methyllithium were added dropwise, the mixture being kept under a nitrogen atmosphere. After stirring for 4 hours, water was added and then the ether layer was separated off and the aqueous layer was extracted with ether. The combined organic layers were dried with NajSÜ4 2% pyridine as eluent chromatographs. 0.30 g of 11 ^ -hydroxy-18-methyl-J ⁵ -estren-3, 17-dione-3,17-diethyienketal-ll /? -Tri-methylsilylether, melting point 168-171 ° C. were obtained. Treatment with concentrated hydrochloric acid in acetone gave 11 / f-hydroxy-l 8-methyl- ^{I 4} -estren-3, l 7-dione.

In a similar way, U # l7 /? - dihydroxy -. ^ ⁵ -estren-3-one-3-ethyienketal-11 /? - trimethylsilyl ether-l7 /? - acetate, j ^ oestren-ii ^^ / f-diol- ll / ^ - trimethylsilylether-U / ii'-acctate, 1 l / y-Hydroxy-J '-östren-U-one - ^ - ethylene ketal-ll / 9-trimethylsilylether and n ^ n ^ -dihydroxy-nrtr-methyl- I ^ -ostrene-S-on-S-ethylene ketal-li ^ -trirnethylsilyläther-17 / f-acetate converted into l1 / ?, l7 _J o'-dihydroxy-18-methyl- / i ⁴ -östren-3-one. 18-MethyM ⁴ -östren-ω \\ ß, \ lß-äi \ o \ ll _J i? -Hydroxy-18- ^{methyl- // 'i} -östren-17-one or 11 / ?, 1 7/9 - Dihydroxy-17A, 18-dimethyl-2f "-östren- 3-one. ■ ■

Example 2

500 mg obtained according to Example Ib) were dissolved in 30 ml of dry ether. 1.0 ml of 20% strength was added to this solution n-Butyllithium in hexane was added under a nitrogen atmosphere and the mixture was then added for 4 hours

Room temperature stirred. Water was added and the organic layer separated. After drying the organic layer over Na2.SO4, the mixture was evaporated and the residue was chromatographed over 45 g of silica gel with toluene / ethyl acetate 9: 1 and 2% pyridine as Klticns. The 11 / -hydroxy-18-n-butyl-z / ' ^i- estren-3,17-dione-3,17-diethylcnketal-l / ^ - trimethylsilyl ether was converted into 1 with concentrated hydrochloric acid in acetone ! / - Hydroxy-18-n-butyl-J ⁴ -estrcn-3,17-dione, m.p. 115-119 ° C.

In a similar manner, the other 1 l / f-trimethylsilyl ether prepared according to Example Ib) were converted into 1 1 /, 17 / -dihydroxy-17-n-butyl-.4 ⁴ -estren-3-one, le-n-butyl- z ^ -ostren-11/17 / ^ 101, 1! / - Hydroxy-18-n-butyl-zf ⁵ -ostren-17-one or 1 1 /, 17 / -dihydroxy-17.'V-meihyl- 18-n-butyl-z / ' ¹ -estren-3-one.

ίο Example 3

a) 1.15 g of I1 / 'Hydroxy-IS-iodo-I''- öslren-SU-dione-SU-diethylcnketal-i 1 / -trimethylsilyl ether were dissolved in 50 ml of diethyl ether which had been dried over KOH. 2 ml of a 1.5 M butyllithium solution in diethyl ether were added to this solution, the reaction mixture being stirred at room temperature for 1 hour. Then 1.5 ml of distilled dimethylformamide was added. A sticky precipitate formed immediately. The mixture was refluxed for an additional hour. Then the mixture was poured into water and extracted with CH> Cb. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue (0.9 g) was chromatographed on 27 g SiCh with toluene / ethyl acetate UU 1: 1 + 2% pyridine as the eluent. In this way, 1 l / ?, 18a-epoxy-18a-hydroxy-18-methyl-z / ^0- estren-3, l7-dione-3, l7-diethylcnketal (= 1 l-hydroxy-18-formyl -z / ⁵ -estren-3,17-dioni 3,17-diethylene ketal cyclohemiacetal), m.p. 144-146 "C (dec.).

The other 18-iodine-l 1 / trimethylsilyl ethers obtained according to Example Ib) were converted in a similar manner into the corresponding 1 i / .lSa-lipoxy-lSa-hydroxy-IB-methyl compounds.

b) 3.4 g of 11 / -hydroxy-18-formyl- / i'-oestrene-3,17-dione-3,17-diethylene ketal (cyclohemi-acetal) were in 33 ml 100% ethanol, 80 ml of diethylene glycol and 33 ml of hydra / .inhydrate suspended. Then there was 6.8 g of hydrazine dihydrochloride admitted. The mixture was brought to 100 ° C. and at this temperature for 16 hours held. The reaction mixture was then cooled to room temperature and then 12 g Powdered sodium hydroxide and 240 ml of diethylene glycol were added. The reaction mixture was on Brought to 200 ° C, with the lower-boiling fractions distilling off. The mixture was left on for 1.5 hours Held 200 ° C and then cooled to room temperature, poured into 2.5 l of ice water with stirring and a stirred for a further hour, and then the resulting precipitate was filtered off until neutral with

Washed water and ^{dried at 70 0} C in a vacuum. After recrystallization from ethyl acetate 2.4 g 1 received / - ^{hydroxy-18-methyl-5} zi -estrene-3,17-dione-3,17-diäthylenketal, mp 178 -181 ⁰ C..

In a similar manner, the other cyclohemiacetals obtained according to Example 3a) were converted into the corresponding liZ-hydroxy-IS-methyl compounds.

Example 4

a) 1.3 g of sodium hydride (55 to 60% suspension in oil) were suspended in 25 ml of dry dimethyl sulfoxide. The mixture was placed in a 75 ° C water bath for 1 hour and then cooled to room temperature. A solution of 10.8 g of methyltriphenylphosphonium bromide in 35 ml of dry DMSO was added to the cooled mixture. After stirring for 15 minutes at room temperature, a suspension of 2.3 g of 11 was /-hydroxy-18-formyl- -estrene-3,17-dione 03.17-diälhylenketal added in 30 ml of dry DMSO <4 ^r '. The entire mixture was stirred in a water bath at 50 ° C. for 6 hours and then poured into 1 l of ice water. The oily residue was filtered through filter aid (Hyflo), washed with water and then for a few minutes with cold methanol / HzO 1: 1.

The filter was washed with methylene chloride, the methylene chloride layer was washed with water, dried over Na2SO4, filtered off and evaporated in vacuo. 2.36 g of 1 l /? - hydroxy-18-vinyl - // ^{5 -estren:} 3.17-dione-3.17-diethylene cctal were obtained.

In a similar manner, the other 1! / - Hydroxy-IS-formyl compounds were obtained according to Example 3a) converted into the corresponding 1! / - hydroxy-ie-vinyl compounds.

b) 100 mg of platinum oxide were prehydrogenated for half an hour in a mixture of 40 ml of methanol / tetrahydrofuran 1: 1. Then 1 g of 11 / -hydroxy-18-vinyl-z / '-östrcn-S. ^ - dione-S. ^ - diethylene ketal and 0.4 ml of 100% acetic acid were added. The 18-vinyl compounds were hydrogenated at room temperature at 1 atm. After 1 mol of hydrogen per mol of steroid had been absorbed, the catalyst was filtered off and the reaction mixture was evaporated. The residue (0.98 g) was purified by chromatography on silica gel (toluene / ethyl acetate 9: 1 + 2% pyridine). This gave II / -hydroxy-18-ethyl -. <4 ' ⁵ -estren-3,17-dione-3,17-diethylene ketal.

Similarly, the other 18-vinyl compounds obtained in Example 4a) became the corresponding ones Hydrogenated 18-ethyl compounds.

Claims (2)

Patent claims: I. Process for the production of H ^ -hydroxy-ie-alkyl-steroids of the Öslran series, characterized in that that one reacts a ll ^ -Hydroxy-13-methyI-gonaitverbindungen with an acyl hypoiodite, the 1 l /? - hydroxy-13-iodomethylgonane compound thus obtained reacts with after protection of the 11 /? an alkali metal alkyl compound or with dimethylformamide in the presence of an alkali alkyl compound and treated the resulting compound with a proton donor and, in the last-mentioned case, the resulting 18-carbaldehyde group reduced or reacted with a Wittig reagent and then the thus obtained 18-alkenyl group reduced. 2. The method according to claim 1, characterized in that 1 mol of a 1! / - Hydroxy-13-methylgonane compound the formula