DE1643084B2 - - Google Patents

Description

(1) The ent-13 / J-lower-alkyl-, -phenyl- or -benzyl-substituted one obtained after step (b) of claim 1 17 "-Hydroxy-8,14-secogona-l, 3, 5 (10), 9-tetraen-14-one acylated,

(2) the ent-13 / J-lower-alkyl, -phenyl- or -benzyl-substitution te 17 "- acyloxy -8,14-secogonal, 3,5 (10), 9-tetraen-14-one with a metal hydride compound reduced,

(3) the ent-13/9-lower-alkyl-, -phenyl- or -benzyl - substituted 17a-acyloxy-8.14-secogonal, 3.5 (10), 9-tetraen-14-ol converts in the presence of an acidic catalyst,

(4) the ent-13/3-lower-alkyl-, -phenyl- or -benzyl-substituted 17a-acyloxy-9,14-oxido-8,14-secogona-1,3,5 (10) -triene hydrolyzed in the presence of an alkali catalyst,

(5) the resulting ent-IS / S-lower-alkyl-, -phenyl- or -benzyl-substituted 9,14-oxido-8,14-secogona-1,3,5 (10) -trien-17-ol oxidized,

(6) the obtained ent-13y? -Lower-alkyI-, -phenyl or -benzyl-substituted 9,14-oxido-8,14-se cogona-1,3,5 (10) -trien-17-one with an acidic egg Bring catalyst into contact, wöbe 130-lower-alkyl-, -phenyl- or -benzyl-sub Substituted Gona-1, 3,5 (10), 8,14-pentaen-17 <x oil is produced and

then steps (d) to (f) according to claim 1 carried out.

The invention relates to a new method for the production of 13 / J-kohlenwasserstoffsubsti tuierten Gona-1,3,5 (10) -trien-17-ones, which is characterized by the fact that one is known per se Methods

(a) a 13 /? - lower-alkyl-, -phenyl- or -benzyl substituted 8,14 - secogona - 1,3,5 (10), 9 - tetraene 14,17-dione reduced with a metal complex,

(b) the compound obtained in this way into a 13 /? - lower-alkyl- -phenyl- or -benzyl-substituted 17a-hydroxy-8,14-secogona-1,3,5 (10), 9-tetraen-14-one and an ent-13 / J-lower-alkyl-, -phenyl- or -benzyl-substituted 17 "-Hydroxy-8,14-secogona-1,3,5 (10). 9-tetraen-14-one separates,

(c) the 13/9 lower alkyl, phenyl or benzyl substituted one 17 "-Hydroxy-8,14-secogona-1,3,5- (10), 9-tetraen-14-one cyclodehydrated in the presence of an acidic catalyst,

(d) the obtained 13 / S-lower-alkyl-, -phenyl- or -ei -benzyl-substituted Gona -l, 3,5 (10), 8,14 - pentaen-17 «-ol with hydrogen in the presence of a Brings reduction catalyst into contact,

(e) the obtained 13 /? - lower-alkyl-, -phenyl- odei -benzyl-substituted gona - 1,3,5 (1O), 8 - tetraene-17λ-ο1 with alkali metal in liquid ammonia implements and

(f) the 13 / J-lower-alkyl-, -phenyl- or -benzyl-sub substituted gona-1,3,5 (10) -triene-17 «-ol is oxidized.

The reason why the partial synthesis replaces the total synthesis in the large-scale production of steroids resides mainly in the difficulty in dealing with a number of diasteroisomers which at the same time either with the cyclization to the formation of the steroid structure or with the saturation of the inter nuclear unsaturated bonds are formed. In more recent times, Hughes and S m i t l a stereoselective overall synthesis of (±) -Östror starting from 5- (m-methoxyphenyl) -pent-l-yne via (±) -Östra-l, 3,5 (10), 8,14-pentaen-17-one described (s Chemistry and Industry 1960, pp. 1022 and 1023, unc Proceedings of Chemical Society 1960, pp. 74 and 75) Furthermore, independently of this, an improved Overall synthesis of 19-nor-steroids by Smith and co-workers [Exporientia, 19, 394 to 396 (1963 No. 8), W i η d h ο 1 ζ and collaborators (Journa of Organic Chemistry, 28, 1092-1094 (1963)]. M i k i and coworkers (Proceedings of the Chemical Society, May 1963, 139) and Crispin et al (Proceedings of the Chemical Societx, 22.1,

1963) reported. Although it was hoped that with this procedure the total synthesis of steroids in the technical Scale could be achieved, the process is still associated with some difficulties.

the. The main difficulty here is that these processes inevitably concurrently a useless steroid isomer is formed. The products of these procedures usually consist of the following four stereoisomers as a result of the orientation of the one attached to the 13- and 17-positions Substituents:

OH

OH

R ²

R *

OH OH R ² J R ² I. \ / \ χ / \

Only the first compound, the substituents in 13 /? - and 17/3 position, can be used as a medicament, while all other isomers are discarded as by-products.

In contrast, the process according to the invention, in which the reduction step is carried out before the intramolecular cyclization, theoretically enables all of the starting material to be used if all the steps are carried out to their full extent. The isomer obtained in stage b) of the process according to the invention, which has the unnatural configuration, is finally converted into compounds of the natural, ie desired, configuration by the corresponding further process steps. It is surprising that the conversion of compounds of the unnatural steroid type into those of the natural steroid type succeeds without further ado if the reduction of the 17-keto group is carried out before the intramolecular cyclization. This was not to be expected, since in the known process, ie when carrying out the reduction of the 17-keto group, the conversion is not possible after the intramolecular cyclization.

The invention is based on the surprising finding that a compound having a 13-substituted 8.14-Secogona-1,3,5 (10), 9-tetraene-14,17-dione nucleus (III), can be easily reduced to a compound that has a (±) 17. \ - hydroxy-13-substituted 8.14 - Secogona -1,3,5 (10), 9 - tetraon -14 - contains one nucleus and essentially a mixture of a compound with a (-) 17 * -hydroxy-13-substituted 8,14-Secogona-l, 3,5 (10), 9-tetraen-14-one core (IV-I) and a compound with a (-! -) 17 * -hydroxy-13 - substituted 8,14 - Secogona -1,3,5 (10), 9 - tetraen-14-one nucleus (IV-II) is where (IV-I) to the natural steroid of Gona-1,3,5 (10) -trien-17-ones or Gona-2,5 (10) -dien-17-one carries out and (IV-II) in the form of Gona-l, 3,5 (10), 9-tetraen-14,17-dione (III) Oxidation of (IV-II) recoverable or in Gona-1,3,5- (10), 8,14-pentaen-17ix-ole (V) can be converted in several stages.

The main object of the invention is accordingly a method for producing a connection that has a (-) 17a-hydroxy-13-substituted 8,14-secogona-1,3, Contains 5 (10), 9-tetraen-14-one core and can be converted into natural 19-nor-steroids. The invention further comprises the preparation of a compound having a 13-substituted 8,14-secogona-1,3,5 (10), 9-tetraene-14,17-dione nucleus contains, by oxidation of a compound which has a (+) 13-substituted 17a-hydroxy-8,14-secogona-1,3,5 (10), 9-tetraen-14-one nucleus contains.

The invention also includes the preparation of compounds which have a (+) 13-substituted one Gona-1,3,5 (10), containing 8,14-pentaen-17 "-ol-kernel, from Compounds which have a (+) 13-substituted 17 * -hydroxy-8,14-secogona-1,3,5 (10), 9-tetraen-14-one-kerr contain.

According to the invention, new compounds are made which have a 13-substituted gona polyenkera included, e.g. B. 13-substituted 17 "-hydroxy-8,14-secogona-1,3,5 (10), 9-tetraen-14-ones, (-) 13-substituted 17 "- hydroxy - gona -1,3,5 (10), 8,14 - pentaene, (-) 13-Substituted 17 "-Hydroxy-gona-1,3,5- (10), 8-tetraene, (+) 13-substituted 17 "-hydroxygona-1,3,5 (10) -trienes etc.

Compounds which have a 13-substituted 8,14-secogona-1,3,5 (10), 9-tetraone-14,17-dione nucleus and are used as starting materials for the overall synthesis according to the invention, are according to methods known per se, e.g. B. by a condensation reaction between 1-hydroxy-l-vinyltetralinen (I) on the one hand and 2-substituted cyclopentane-1,3-dione (II) on the other hand.

ao 1-Hydroxy-l-vinyltetraline have the following all common structure:

CH - CH2
Λ OH

R ¹

herein, R ^{1 is} a hydroxyl group, etherified hydroxyl group (e.g. methoxy, ethoxy, benzyloxy) or esterified hydroxyl group (e.g. acetyloxy, nicotinoyloxy). The compounds can, for example, at one or more of the positions 3, 4, 5, 7 and 8 in the tetralin skeleton by a hydrocarbon radical, e.g. B. a lower alkyl radical (for example methyl, ethyl, n-propyl, isopropyl, n ^ butyl and isobutyl), phenyl or benzyl radical and / or at one or more of the positions 5, 6, 7 and 8 in the skeleton by a hydroxyl group, an etherified hydroxyl group (e.g. methoxy, ethoxy, n-propoxy and n-butoxy), an esterified hydroxyl group (e.g. acetoxy, propionyloxy and benzoyloxy), a halogen (e.g. fluorine and chlorine), a thio group (e.g. Mercapto, Me-

ethylthio, ethylthio and acetylthio) and an acyl radical (e.g. acetyl, propionyl and benzoyl) may be substituted. The 2-substituted cyclopentane-1,3-diones have the following general structure:

\ / 3 \ 2 4

¹ Here, R ² , the substituent in the 2-position, is a lower alkyl radical (for example methyl, ethyl, n-propyl, isopropyl, η-butyl and isobutyl), phenyl or benzyl. Of the hydrogen atoms in the 4 and 5 positions of these 2-substituted cyclopentane-1,3-diones, 1 to 3 can furthermore be replaced by 1 to 4 hydrocarbon radicals of the type mentioned above.

The first stage of the process according to the invention consists of a selective reduction of a compound which contains a 13-substituted 8,14-Secogona-1,3, 5 (10), 9-tetraene-14,17-dione nucleus (III), wherein

a compound is formed which has a (±) 13-substituted 17 "-hydroxy-8,14-secogona -1,3,5 (10), 9-tetraen-14-one nucleus (IV) and is essentially a mixture of (IV-I) and (IV-II).

The compound (III) can be converted into the compound (IV) by reduction with a specific reducing agent. The reducing agents which are used for the reduction of (III) into the corresponding tetraenols (IV) must be able to convert a carbonyl into a carbinol without attacking the C - C double bonds. Preferred reducing agents include metal complexes, e.g. B. alkali borohydrides (e.g. lithium borohydride, sodium borohydride and potassium borohydride), alkali aluminum hydrides (e.g. lithium aluminum hydride, sodium aluminum hydride and potassium aluminum hydride), diethyl aluminum hydride and aluminum isopropoxide. The reaction is usually carried out in a solvent. The usual organic solvents are suitable as solvents as long as they do not interfere with the reaction. For example, methanol, ethanol, n-propanol, isopropanol, n-butanol, tetrahydrofuran, dioxane, ether, petroleum ether, chloroform, benzene and toluene are suitable. The hydride type reducing agents exemplified above are generally used with the compounds (III) at a fairly low temperature, e.g. B. at temperatures that are below room temperature (about 20 to 25 ⁰ C), but above about -60 ° C, while the reaction of the reducing agent of the alkoxide type expediently accelerated by heating and usually in boiling isopropanol or ethanol, both as Solvent as well as being effective as a reaction component is carried out.

The compounds (IV) prepared in this way are new and valuable for the purposes of the invention. They have the following general structure:

OH

and

(IV-II)

R ¹

R ¹ and R ² have the same meaning as mentioned above in connection with formulas (I) and (II), and can contain one or more substituents which correspond to the starting compounds (I) and (II). The compounds (IV) prepared in the manner described above are essentially a racemic mixture consisting of the following two stereoisomers:

OH
R ₂

R ¹

Thus, in order to obtain an optically active product, the racemic resolution is necessary. In particular in the context of the invention, the aforementioned racemic mixture of the compounds (IV-I) and (IV-II) preferably subjected to racemic resolution because the undesired isomer is converted into a Compound having a 13-substituted 8,14-secogonal, 3,5 (10), 9-tetraene-14,17-dione nucleus (III) contains, or a desired compound which contains a 13-substituted gona-1,3,5 (10), 8,14-pentaen-17 «-ol nucleus, is converted. Both methods will

as described later. The racemic resolution described below is applicable to all compounds containing such a nucleus, e.g. B. a (±) 13-substituted gona-1, 3.5 (10), 8,14-pentaen-17a-ol-kernel (V), a (±) 13-substituted gonal, 3.5 (10) , 8-tetraene-17'-ol nucleus (VI), a (±) 13-substituted gona-l, 3,5 (10) -trien-17a-ol nucleus (VII) and a (±) 13- substituted Gona-2,5 (10) -diene-17 «-o1-core. In general, however, the racemic resolution is preferably carried out as early as possible.

In the process according to the invention, the racemic resolution is easily carried out by utilizing the im general 17 "hydroxyl group present. One way to carry out the racemic Separation is via an optically active ester of the steroid, and another option is enzymatic Hydrolysis of an acylated derivative of the product.

In the first method of racemic resolution, the 17 "-hydroxysteroids are allowed to react with an optically active acid or its halide, e.g. B. 1-menthoxyacetic acid or its chloride or bromide, react, a mixture of the corresponding diastereomers being obtained. B. by fractional recrystallization, and hydrolyzed to obtain the optically active 17a-oils. Instead of acylating with an optically active acid, the 17 <x -ol can be acylated with a dibasic acid, e.g. B. succinic acid, phthalic acid or sulfobenzoic acid, using their reactive derivative, e.g. B. of anhydride or a chloride, esterifying the corresponding half-ester, whereupon salts with an optically active base, e.g. B. ephedrine, strychnine and brucine forms.
In another method of racemic resolution, the 17 «-01 is acylated in the usual way, the 17-acylate, z. B. the acetate, acetoacetate, glycinate. Diethylaminoacetate, memisuccinate and hemiadipate. (TV-I) is obtained. The acylate obtained is an enzyme

subjected to matic hydrolysis in an aqueous medium which allows hydrolysis, e.g. B. diastasis, Lipase and tripsin. The method for carrying out the enzymatic hydrolysis is in dei U.S. Patent 3,094,465. The hy-

(IV)

Drolysis and the production of steroids can be carried out in the manner described there. Certain microorganisms, which are able to form this hydrolysis can come into direct contact with the 17-acylates to be brought. Examples of such microorganisms are those of the genera Rhizopus and Aspergillus.

As examples of the compounds thus obtained which have a 13-substituted na-hydroxy-S.M-secogonal, 3,5 (10), 9-tetraen-14-one nucleus include:

(H-) or (-) 17ix-hydroxy-8,14-secoöstra-l, 3,

5 (10), 9-tetraen-14-one,
(+) or (-) 17 «-hydroxy-3-methoxy-8,14-seco-

östra-l, 3.5 (10), 9-tetraen-14-one,
(+) or (-) 17 * -Hydroxy-3-ethoxy 8,14-seco-

östra-l, 3.5 (10), 9-tetraen-14-one,
(+) or (-) 17oi-Hydroxy-13-ethyl-8,14-seco-

gona-l, 3,5 (L0), 9-tetraen-14-on,
(+) or (-) 17a-Hydroxy-13-isopropyl-8,14-se-

cogona-l, 3.5 (10), 9-tetfean-14-on,
(+) or (-) 17 «-Hydroxy-13-benzyl-8,14-seco-

gona-l, 3.5 (10), 9-tetraen-14-one,
(+) or (-) l ^ a-Hydroxy-lS-phenyl-eH-seco-

gona-l, 3.5 (10), 9-tetraen-14-one,
(+) or (-) Na-Hydroxy ^ -methoxy-lS-ethyl-

8,14-secogona-l, 3,5 (10), 9-tetraen-14-one,
(+) or (-) na-hydroxy ^ -methoxy-Bn-pro-

pyl-8,14-sec: ogona-l, 3,5 (10), 9-tetraen-14-one,
(+) or (-) 17 «-hydroxy-3-methoxy-13-iso-

propyl-8,14-secogona-1,3,5 (10), 9-tetraen-14-one, (+) or (-) 17 «-hydroxy-3-methoxy-13-phe-

nyl-8,14-secogona-l, 3,5 (10), 9-tetraen-14-one,
(+) or (-) 17 "-Hydroxy-3-methoxy-13-benzyl-8,14-secogona-1,3,5 (10), 9-tetraen-14-one.

The second stage of the overall synthesis according to the invention is an intramolecular cyclization of the compounds (IV-I), which form the end of the ring C to The consequence is that compounds are formed which have a (-) 13-substituted 17 "-Hydroxygona-1,3,5- (10), 8,14-pentaen-17-one nucleus (V) included.

The cyclization is accelerated by use an acidic catalyst. Suitable catalysts are, for example, inorganic acids or their anhydrides (2: B. hydrochloric acid, sulfuric acid, phosphoric acid, phosphorus pentoxide and polyphosphoric acids Hydrogen salts or partial esters of these polybasic inorganic acids (e.g. sodium hydrogen sulfate, Monosodium hydrogen phosphate and monomethyl sulfate), their pyridine complexes (e.g. pyridine-hydrobromic acid complex), Sulphonic acids (e.g. methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid and toluenesulfonic acid), sulfonated cation exchange resins of the styrene type, so-called Lewis acids (e.g. aluminum chloride, boron trifluoride and tin chloride) and silica gel.

This reaction does not require a solvent. However, it can be smoother using a suitable solvent, e.g. B. benzene, toluene, xylene, tetrahydrofuran, dibutyl ether, methanol, ethanol and propanol can be carried out. The reaction is also accelerated by bath and takes place easily with mild heating. If necessary, the reaction can also ^{be carried out in the vicinity of 100 °} C. or above.

The reaction of this stage appears to be via 14-Hydroxygona-1,3,5 (10), 9-tetraen-17a-ols as intermediate compounds take place because such mild conditions as the use of silica gel, often the Formation of these interconnections cause that through further contact with a fairly Let the strong acid catalyst easily convert into the desired compounds (V).

The compounds obtained, which have a 13-substituted gona-1,3,5 (10), 8,14-pentaen-17a-ol-kern (V) have the following general structural formula:

OH
R ² i

J = -

R ¹

Here, R ¹ and R ^{2 have} the meaning mentioned, including the substituent or substituents which correspond to the starting compounds if these are substituted, ie somewhere in the 1, 2, 3, 6, 7, 15 and 16 positions there are one or more Hydrocarbon radicals, examples of which have been given in connection with compounds (1) and (II), and / or at any of the positions 1, 2 and 3 are hydroxyl, etherified hydroxyl, esterified hydroxyl, halogen and thio, as in connection with the compounds (I) indicated. For example, are particularly advantageous for this purpose

(+) or (-) Östra-1, 3,5 (10), 8,14-pentaen-17a-

oil,
(+) or (-) 3-Methoxyöstra-1,3,5 (10), 8,14-pentaen-17 «-ol,

(+) or (-) Äthoxyöstra-1,3,5 (10), 8,14-pentaen-17a-ol,

(+) or (-) 3-n-Propoxyöstra-1,3,5 (10), 8,14-

pentaen-17oc-ol,
(+) or (-) 13-Ethylgona-1,3,5 (10), 8,14-pentaen-17a-ol,
(+) or (-) 13-Isopropylgona-l, 3.5 (10), 8.14-

pentaen-17 "-ol,
(+) or (-) 13-Phenylgona-1,3,5 (10), 8,14-pentaen-17 «-ol,

(+) or (-) 13-Benzylgona-1,3,5 (10), 8,14-pentaen-17a-ol,

(+) or (-) 3-Methoxy-13-ethylgona-l, 3,5 (10),

8,14-pentaen-17oc-ol,
(+) or (-) S-methoxy-Dn-propylgona-IS, 5 (10), 8,14-pentaen-17 «-ol,
(+) or (-) 3-Methoxy-13-phenylgona-l, 3, 5 (10), 8,14-pentaen-17ot-ol,

(+) or (-) 3-Methyl-13-benzylgona-1,3,5 (10), 8,14-pentaen-17 «-ol.

All the compounds mentioned as examples show characteristic ultraviolet absorption bands in the range of wavelengths of about 310 ταμ.

The connections (V) are key connections in the method according to the invention, since they are shown has that they are stereoselectively and exclusively into the corresponding 13-substituted gona-1,3,5 (10), 8-tetraen-17oc-ols (VI) can be converted in which the hydrogen bonded to the 14-position

409530/415

ίο

is oriented towards the «configuration, d. H. to the same all compounds mentioned above as examples

Configuration like estrogen steroids, which from natural show characteristic absorption bands in

borrowed sources. Wavelength range from about 273 to 281 πιμ.

The transformations of the compounds (V) into compounds The compounds (VI

bonds (VI) are expediently carried out by so-called 5 are subjected to a further reduction in order to dii

catalytic reduction. For this purpose, pre-double bond in the 8-position is to be saturated. Dii

preferably Raney nickel or palladium as catalyst reduction is preferably carried out in such a way that

sator used. The reaction can in a suitable one an alkali metal with the compounds (VI) ii

Solvent, for example dioxane, tetrahydrofluid ammonia converts. As an alkali metal!

Furan, ether, methanol and acetic acid, carried out io, are, for example, lithium, sodium and unc

will. She usually finds potassium at room temperature. The reaction takes place in liquid ammonial

instead, but can optionally also with increased or its mixture with an inert solvent

or at a lower temperature. In carried out. Siel are suitable as inert solvents

in any case, conditions that are too strict for this purpose, for example ether, dioxane, and unc

Reaction can be avoided as a further hydrogenation 15 tetrahydrofuran. Because the agent is pretty violent

tion can take place at positions 8 and 9, where the reaction is usually at a lower temperature

by having the opposite configuration of the ratur, e.g. B. below room temperature, up to £

Hydrogen at the 8-position in the product results in -30 ° C,

can. This way you will be in good overall profit

The compounds (VI) prepared in this way include 13-substituted gona-1,3,5 (10) -triene-17'-ols (VII) ge

are also new and valuable for the purposes of forms to which estradiol or its related ver

Invention. They have the following general formula: bonds as well as a number of new compounds

belong, which also show estrogen activity unc

OH have the following general formula:

OH
R ² :

/ ■ \ J% / ' ^(VI) ( Ί ^{/ Χ |}

R ¹

Here, R ¹ and R ^{2 have} the abovementioned range

interpretation. You can also, for example, at the 1-, 2-, Here, R ¹ and R ^{2 have} the aforementioned Be-3-, 6-, 7-, 15- or 16-position one or more meanings. The compounds can have the hydrocarbon radical or radicals of the compounds (VI) used in connection with the same substituents as the type and / or position mentioned for their herds of compounds (I) and (II).
a hydroxyl group in the 1-, 2- or 3-position, 40 The compounds (VII) prepared in this way can contain etherified hydroxyl groups (e.g. methoxy, ethoxy, saturation of the double bond on the aromatic ring propoxy and butoxy) and an esterified hydroxyl - Are reduced, a compound containing gebildel group, halogen and thio, as is described together, a 13-substituted gona-2,5 (10) -dienmenhang with the compounds (I). Be 17 «-ol core (VIII) contains. The reduction can be carried out especially preferably for the purposes of the invention, by adding an Al, for example: potassium metal with the compounds (VII) in liquid

Converts ammonia, which is a source of protons, e.g. B.

(+) or (-) östra-l, 3,5 (10), 8, tetraen-17a: -ol, an alcohol with up to 6 carbon atoms, for example

(+) or (-) 3-Methoxyöstra-1, 3.5 (10), 8, tetraene-methanol, ethanol, tert-butanol, etc., contains, while

17 «-ol, _ so rend the other conditions are the same as

(+) or (-) 3-Äthoxyöstra-1,3,5 (10), 8-tetraen- mentioned above. In the same way as with

17 «-ol, this reaction can be the compound that one

(+) or (-) 13-Ethylgona-l, 3,5 (10), 8-tetraen-13-substituted l, 3,5 (10), 8-tetraen-17a-ol-kern (VI)

17λ-ο1, also converted into the same product (VIII)

(+) or (-) 13-Isopropylglygona-1,3,5 (10), 8-th- 55, whereby the double bond in the 8-place

traen-17 «-ol, lung and the double bond on the aromatic ring

(+) or (-) 13-Phenylgona-1,3,5 (10), 8-teraen- is saturated.

17 <x-ol, The trienols (VII) obtained in this way can be converted into one

(+) or (-) 13-Benzylgona-1,3,5- (10), 8-tetraene-compound, which has a 13-substituted gona-triene-

17 «-ol, 60 contains 17-one nucleus (X), and the dienols (VIII) to

(+) or (-) 3-Methoxy-13-äthylgona-1,3,5 (10), lead compounds which have a 13-substituted one

Contains 8-tetraen-17 * -ol, Gona-dien-17-on-kern (IX). Both connections

or (-) S-methoxy-n-isopropylgona-l.S, fertilizers have the configuration of estrogen-

5 (10), 8-tetraen-17 «-ol, steroids obtained from natural sources

(-f) or (-) S-Methoxy-D-phenylgona-l ^, 65 become.

5 (10), 8-tetraen-17 «-ol, The reaction can, for example, by the Oppen-

(- | -) or (-) 3-Methoxy-13-benzylgona-1,3,5 (10), auer-oxidation using aluminum

8-tetraen-17a-ol. isopropoxide, aluminum ethoxide, Alumi.iiumph-

oxide, pyridine-chromic anhydride, etc., by oxidation using pyridine chromic anhydride or dimethyl sulfoxide dicyclohexylcarbodiimide, by oxidation using microorganisms, etc. These reactions are preferably carried out under neutral or alkaline conditions.

All of the above reactions are applicable to racemic mixtures as well as optical isomers. However, as mentioned earlier, it is preferable to use the compound containing a (±) 13-substituted 17a-hydroxy-8,14-secogona-1,3,5 (10), 9-tetraen-14-one nucleus (IV) to subject to optical separation for the purpose of obtaining the unnatural compound which contains a (+) 13-substituted 8,14-Secogona-1,3,5 (10), 9-tetraene-17 * -ol nucleus (IV-II ).

This recovery process is carried out by treating the compound (IV-II) with an oxidizing agent reacted, whereby a compound is obtained which has a 13-substituted 8,14-secogonal, 3,5 (10), 9-tetraene-14,17-dione nucleus contains (III). The oxidizing agents suitable for this reaction must be able to convert the hydroxyl group to the oxo group to oxidize without attacking a C - C double bond. Preferred oxidizing agents are, for example Chromic acid, aluminum alkoxide and ketones (Oppenauer oxidation), dimethylsulfoxide-dicyclohexylcarbodiimido etc. The thus obtained stcodione (III) can be used as starting materials for the Methods according to the invention can be used.

As an alternative, the compounds containing a (+) 13-substituted 8,14-Secogona-1,3,5 (10), 9-tetraene-17 «-ol nucleus contain (IV-II), are converted into compounds which have a (-) 13-substituted Gona-l, 3,5 (10), 8,14-petnaen-17 * -ol-kern (V), in which the substituent attached to the 13-position is oriented towards the jS configuration. This is the same configuration as that of estrogen steroids obtained from natural sources. The conversion process includes the following stages:

1) The Secotetraen-17 * -ol compounds are used (IV-II) with a customary acylating agent to compounds which have a (+) 13-substituted n ^ -Acyloxy-S.M-secogona-l ^ SQO ^ -tetraen-14-on-kern included (XI).

2) The (+) 17 »-hydroxy-secotetraenones thus obtained are reduced (XI) with a metal hydride compound to a compound which has a (+) 13-substituted 17 "-acyloxy-8,14-secogonal, 3,5 (10), 9-tetraen-14-ol-nucleus contains (XII). The reaction conditions at this stage are the same as those in the reduction process of Secodionen (III) to Seco-17 »-ols (IV) can be used.

3) The 17'-acyloxy-secoenols (XII) obtained in this way are combined with an acidic catalyst, whereby compounds are obtained which have a (+) 13-substituted 17a-acyloxy-9, 14-oxido-8,14-secogona-1,3,5 (10), 9-tetra-core included (XIII). The reaction conditions in this stage are similar to those in the cyclization process from secotetraenols (IV) to pentaenols (V) can be used.

4) The 17 "acyloxy-oxides (XIII) obtained in this way are hydrolyzed to give compounds which have a (+) 13-substituted 9,14-oxido-8,14-secogona-1,3,5 (10), 9-tetraen-17-ol nucleus included (XIV). Any conventional conditions are suitable for the hydrolysis. For example can in the presence of alkali hydroxides (sodium hydroxide, potassium hydroxide), hydroxylase (e.g. maltase, diastase) etc. can be worked.

5) The oxido-tetraenols (XIV) obtained in this way are oxidized to compounds which have a (-) 13-substituted one 9.14 - Oxido - 8.14 - secoöstra -1,3,5 (10), contain 9-tetraen-17-one nucleus (XV). This reaction can be carried out under the same conditions as above for oxidation of trienols (VII) or dienols (VIII) to trienones (X) or dienones (IX) and that Recovery process with oxidation of (+) secotetraenols (IV-II) to secodionen (III) called became.

6) The finally obtained oxido-17-ones (XV) are combined with an acid catalyst, whereby compounds are obtained which have a (-) 13-substituted gona-1,3,5 (1O), 8, Contains 14-pentaen-17a-ol core. This cyclization reaction can be carried out under the same conditions as in the cyclization of secotetraenols (IV-I) to pentaenols (V) can be applied.

In the following examples all temperatures are uncorrected. The percentages relate to the weight.

Example 11

1) (±) 3-Methoxy-17 * -hydroxy-8,14-secoestra-1,3,5 (10), 9-tetraen-14-one

To a solution of 2 g of 3-methoxy-8,14-secoestral, 3,5 (10), 9-tetraene-14,17-dione 0.08 g of sodium borohydride are added to 100 ml of methanol while cooling with ice. The mixture is among the same Conditions stirred. After 2 hours, the reaction solution is treated with a mixture of water and ether shaken out. The ether layer is washed with water and dried. After the 1.8 g of (±) 3-methoxy-17 «-hydroxy-8,14-secoestra-1,3,5 (10), 9-tetraen-14-one become solvent obtain. The product is recrystallized from a mixture of ether and hexane, giving the pure product with a melting point of 74 ° C.

Elemental analysis for C ₁₉ H ₂₄ O ₃ :

Calculated ... C 76.00, H 8.00;
Found ... C 76.27, H 7.92.

Ultraviolet Absorption: /

j ethanol

266 ηιμ (ε = 19300)

2-1) (+) 3-methoxyöstra-1,3,5 (10), 8,14-pentaen-17λ-ο1

To a solution of 1.7 g (±) 3-methoxy-17Ä-hydroxy-8,14-secoöstra-1,3,5 (10), 9-tetraen-14-one 5 ml of 6N hydrochloric acid are added to 50 ml of methanol. The mixture is left to stand for 2 hours at room temperature, whereupon it is shaken out with a mixture of water and ether. The ether layer is with an aqueous solution of sodium hydrogen carbonate and then washed with water, dried and used for Evaporated removal of solvent. The residue is chromatographed on a column with 80 g of silica gel is filled. After elution with a mixture of benzene and ether (9: 1), the

1

2-2) (±) 3-methoxyestra-1,3,5 (10) .8,14-pentaen-17% - ol

To a solution of 1 g (±) 3-methoxy-17 & -hydroxy-8,14-secoöstra-1,3,5 (10) -9-tetraen-14-one 7 ml of concentrated hydrochloric acid are added to 50 ml of methanol. The mixture is refluxed for 30 minutes heated and then shaken out with a mixture of water and ether. The ether layer is made with a aqueous solution of sodium hydrogen carbonate and then washed with water, dried and removed to remove evaporated the solvent, whereby 0.8 g (±) 3-Methoxyöstra-I, 3,5 (10), 8,14-pentaen-17 «-ol as yellowish oil can be obtained.

3) (±) 3-Methoxyestra-1,3,5 (10), 8-tetraen-17 «-ol

A solution of 0.9 g (±) 3- '
(10), 8,14-pentaen-17a-ol in 80 ml of dioxane is subjected to catalytic hydrogenation in the presence of 1 g of Raney nickel. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to give a residue from which 0.5 g of crystals of (±) 3-methoxyestra-1,3,5 (10), 8-tetraen-17 «-ol can be obtained. The crystals are recrystallized from ethyl acetate. Melting point 161 ⁰ C.

Elemental analysis for C ₁₈ H ₂₁ O ₂ :
Calculated ... C 80.2 », Jd 8.45,
found ... C 79.9-1 , H 8.41. 0843

Ultraviolet absorption: λ

ÄLnanoi

277πιμ (ε = 15700).

4) (±) 3-Methoxyestra-1,3,5 (10) -triene-17 «-ol

To a solution of 0.4 g (±) 3-methoxyestra-1, 3.5 (10), 8-tetraene-17 “-ol in a mixture of 70 ml of liquid ammonia, 20 ml of dioxane and 40 ml of ether Add 0.7 g of potassium metal while cooling to -5 ° C. The mixture is 2 hours stirred under the same conditions. To the reaction solution 2 g of amoinum chloride are given. the The resulting solution is left to stand at room temperature to remove the ammonia. To the arrears is given water. The mixture is extracted with ether. The ether layer is washed with water, dried and concentrated. The residue

Eluate 1.2 g (rb) S-methoxy ^ l ^ oxido-S ^ secoöstra-I ₅ 3.5 (10> trien-17-one obtained. Melting point 83 ° C.

Elemental analysis for C ₁₈ Hg ₁ O ₃ :

Calculated ... C 76.00, H 8.00; found ... C 75.88, H 7.97.

Ultraviolet absorption: λ ££ """ma (ε) 225 (8850)

275 (1690)
282 (1665)

Infrared absorption: ν ^ ^ol cm- ¹ 1740.

7 ml of concentrated hydrochloric acid are added to a solution of 1.1 g of the oxide thus obtained in 50 ml of methanol. The mixture is refluxed for 30 minutes, after which it is extracted by shaking with a mixture of water and ether. The ether layer is washed with an aqueous solution of sodium hydrogen carbonate and then with water, dried and evaporated to remove the ether, 1 g of (±) 3 - Methoxyöstra -1,2,5 (10), 8.14 - pentaene -17 - oil is obtained as a yellowish oil.
Ultraviolet absorption: λ i ¹ ^ "" ¹ 311 ΐημ (ε = 20000) Infrared absorption: ν Tnracmorm «han 3400 _cm- i
(OH)

is recrystallized from hexane, whereby 0.2 g of (±) 3-Methoxyöstra4l, 3,5 (10) -trien-17Ä-ol in the form of crystals with a melting point of 94 ° C.

Elemental analysis for C ₁₉ H ₂₈ O ₈ :

Calculated ... C 79.72, H 9.09; Found ... C 79.98, H 9.15.

Ultraviolet absorption: λ £ ax ^anxl 280 πιμ (ε = 1980)

288 mfi. (ε = 1900)

5) (+) 3-Methoxyestra-1,3,5 (10) -trien-17a-one

To a solution of 0.2 g (±) 3-methoxyestral, 3.5 (10) -triene-17 <x-ol in 10 ml of acetone are added with stirring to 0.2 ml of a solution that is prepared had been added by adding 26.72 g of chromic anhydride and 23 ml of concentrated sulfuric acid in such a Amount of water were dissolved so that the total volume was 10 ml. The mixed solution is 20 minutes left to stand at room temperature. Water is added to the reaction solution and crystals are precipitated , which are recrystallized from methanol, 0.15 g of (±) 3-Methoxyöstra-1,3,5 (10) -trien-17-one with a melting point of 140 ° C.

6) (+) 3-Methoxyestra-2,5 (10) -diene-17 «-ol

To a solution of 1 g (±) 3-Methoxyöstra-1,3,5- (10), 8-tetraen-17 «-ol in a mixture of 50 ml

Dioxane, 50 ml of ether and 150 ml of liquid ammonia which is cooled to -50 ⁰ C, are added 2 g of metallic lithium. The mixture is stirred. After 30 minutes, 50 ml of ethanol are added dropwise to the reaction solution, and the resulting solution is left to stand at room temperature to remove the ammonia. The residue is extracted with a mixture of water and ether. The ether layer is washed with water, dried and evaporated to remove the solvent, crystals of (±) 3-methoxyöstra-2,5 (10) -diene-17λ-ο1 being obtained, which are recrystallized from a mixture of ether and hexane . Colorless needles with a melting point of 119 ^° C. are obtained in a yield of 0.6 g.

7-1) (±) 3-methoxyestra-2,5 (10) -dien-17-one

In a solution of 1.5 ml of benzene, 1.5 ml of dimethyl sulfoxide, 0.8 ml of pyridine and 0.04 ml of trifluoroacetic acid are 0.2 g of (±) 3-methoxyestra-2,5 (10) -dien-17 «-ol solved. The resulting solution is mixed with 0.62 g of dicydonexylcarbodiimide and 6 hours at Left to stand at room temperature. A solution of 25 ml of ether is then added to the reaction mixture. 0.3 g of oxalic acid and 6 ml of methanol were added. The mixed solution is left to stand. After 30 minutes the dicyclohexylurea formed is filtered off and the ether layer is separated from the Hltrat. The ether layer is washed with an aqueous solution of sodium hydrogen carbonate and then with water, dried and evaporated to remove the solvent. The residue is made from ethanol recrystallized, leaving 0.18 g (±) 3-methoxyestra-2,5 (lU) -dien-17-one with a melting point of 115 ° C.

Elemental analysis for C ₁₉ H ₂₆ O ₂ :

Calculated ... C 79.68, H 9.15, found ... C 79.53, H 9.22.

7-2) (±) 3-Melhoxyostra-2,5 (10) -dien-17-one

In a solvent mixture of 2 g of cyclohexanone and 50 ml of toluene, 0.2 g of (±) 3-methoxyestra-2,5 (10) -dien-17 «-ol are added solved. The solution obtained is concentrated to 20 ml. 0.2 g of aluminum isopropoxide are added to the solution. The mixture is refluxed for 3 hours. After adding 30 ml of water to the reaction solution, the mixture becomes subjected to steam distillation after neutralization with dilute sulfuric acid. Of the The residue is extracted with ether. The ether layer is washed with water, dried and removed to remove evaporated the solvent. The residue is recrystallized from hexane, 0.1 g (±) 3-Methoxyestra-2,5 (10) -dien-17-one in the form of Crystals with a melting point of 115 ° C are obtained.

Infrared absorption: ν ™ * 1743 cm " ¹ (C = O)

Example 2

1) (±) 3-Methoxy-13/3-ethyl-17 "-hydroxy-8,14-secogona-1,3,5 (10) -9-tetraen-14-one

0.08 g of sodium borohydride are added to a solution of 1.3 g of 3-methoxy-l ^ -ethyl-8 14 ^ ecogona-l, 3,5 (10), 9-tetracn.14,17-dione in 80 ml of methanol given while chilling with ice. The mixture is stirred under the same conditions. After 2 hours, water and ether are added to the reaction solution. The mixture is shaken, whereupon the ether layer is separated. The ether layer is washed with water, dried and evaporated to remove the solvent, 1.3 g of a yellowish oily residue of (±) 3-methoxy-Vyyy.g..iW
traen-14-on can be obtained. The oil is purified by chromatography on silica gel.

Infrared absorption: ν ^ ¹ 3400, 1735 cm- ¹

2-1) (±) 3-methoxy-13/9-ethylgona-1, 3.5 (10), 8,
14-pentaen-17a-ol

To a solution of 0.5 g (±) 3-methoxy-13E-ethyI-17a-hydroxy-8,14-secogona-1,3,5 (10), 9-tetraen-14-one 5 drops of concentrated hydrochloric acid are added to 40 ml of methanol. The resulting solution is 2 hours left to stand at room temperature. The reaction solution is then shaken out with water and ether, whereupon the ether layer is separated. The ether layer is with an aqueous solution of Sodium hydrogen carbonate and then washed with water and evaporated to remove the solvent The residue is chromatographed on a column, which is filled with 20 g of silica gel. The eluate obtained with a mixture of benzene and ether (9: 1) is concentrated, whereby 0.2 g (± 31 3-methoxy-9 14-oxido-13 ^ -ethyl-8,14-secogona-1,3,5 (10) -irien-17-one with a melting point of 64 ° C.

Elemental analysis for C ₂₀ H ₂₆ O ₃ :

η »" ι ... η nc αϊ Lion.
Calculated ... C 76.43, H 8.33:

geiunaen ... ^ 10,31, ti ö.jj.

To a solution of 0.1 g of (±) 3-methoxy-9,14-oxido-13 / S-ethyl-8,14-secogona-1,3,5 (10) -trien-17-one 1 ml of concentrated hydrochloric acid is added to 10 ml of methanol. The mixture is refluxed for 30 minutes

heated. The reaction solution is then extracted with a mixture of water and ether, whereupon the ether layer is separated. The ether layer is coated with an aqueous solution of sodium hydrogen carbonate and then washed with water and dried. The ether layer is used to remove the Evaporated solvent, leaving 0.1 g (±) 3-methoxy-13 /? - äthylgona-l, 3.5 (10), 8,14-pentaen-17ix-ol is obtained as a yellowish oil.

Ultraviolet absorption: λ ££? ^no1 309 ma (ε = 20,000) Infrared absorption: ν £ ^CM 3400cm " ¹

£ ^CM 3400cm "

2-2) (±) 3-methoxy-13/9-ethylgona-1, 3,5 (10), 8,14-pentaen-17 "-ol

To a solution of 1 g (±) 3-methoxy-13/3-ethyl-17a-hydroxy-8,14-secogona-l, 3,5 (10), 9-tetraen-14-one In 40 ml of methanol, 10 ml of concentrated salt

ao acid given. The mixture is refluxed for 30 minutes. After adding water and ether to the reaction solution, the mixture obtained is shaken out, whereupon the ether layer is separated off. The Atherschicht is washed with an aqueous solution of sodium hydrogencarbonate and with water, _getrockn et and removing the solvent, a _{gedampft5 where 0,} 9 g of (±) 3-Methoxy-13, S-äthylgonai, 3 _j5 (io), 8.14 -pentaen-17 «.ol can be obtained as a yellowish oil

<±) 3-Methoxy-13 ^ ethylgona-1,3,5 (10), 8-tetraen-1 / a-ol

_{A lo of 0 9 (±) 3} . _M ethoxy-13i? -Äthyl _gon al, 3.5 (10), 8.14-pentaen-17 _Ä -ol in 80 ml of dioxane _{is the catalytic} hydrogenation in the presence of _{0 5 Rane} y. _N ickel subjected. The reaction solution _{is then filtered to separate off the} catalyst.

_{The filtrate is} concentrated under reduced pressure, crystals of (±) 3-methoxy-13 ^ -äthylgonal, 3,5 (10), 8-tetraen-17 * -ol being precipitated. The crystals are recrystallized from methanol. Melting point 141 to 143 ^° C. Yield 0.6 g.

Elemental analysis for C ₂₀ H ₂₆ O ₂ :

Calculated ... C 80.49, H 8.78;
Found ... C 80.36, H 8.64.

Ultraviolet absorption: λ £ Γ 275 ΐημ (ε = 16400)

⁴ ) (±) 3-Methoxy-13i? -Äthylgonal, 3,5 (10) -trien-17a-ol

_{In dnem Gem S} ch i of 40 ml liquid ammonia _{and dioxane 1Oml 0,} 3 g of (±) 3-Methoxyi _{be 3} ". _ä thylgona-l, 3,5 (10), 8-tetraene-17-ol dissolved _Ä. The _v £ _{is au {} _ ₅₀ c _{C cools to the chilled lo} .

_{05 metallic} potassium are added, _{whereupon the} mixture is stirred for 2 hours. After adding ₂ ammonium chloride, the reaction _{solution obtained is left to stand} at room temperature to remove the ammonia. The residue is mixed with water and extracted with ether. The ether layer is washed with water, dried and evaporated ^ removal of the solvent. The residue is recrystallized from an aqueous methanol solution, 0.1 g of (±) 3-methoxy-13 /? - äthylgona-1,3,5 (10) -trien-17 “-ol in the form of crystals with a melting point of 71 to 73 ⁰ C is obtained.

5)

+) 3-methoxy-13 /? - ethylgonal, 3,5 (10) -trion-17-one

0.2 ml of an aqueous solution are added to a solution of 0.02 g of (±) 3-methoxy-13 /? - äthylgona-1,3,5 (10) -trien-17a-ol in 5 ml of acetone 26.72 g of chromic anhydride and 23 ml of concentrated sulfuric acid per 100 ml, followed by stirring. The reaction solution is left to stand for 20 minutes at room temperature and water is added, crystals being precipitated which are recrystallized from methanol, 0.015 g of (±) 3-methoxy-13/3-ethylgona-1,3,5 (10) -triene -17-ün with a melting point of 128 ⁰ C can be obtained.

6) (±) 3-Methoxy-13 /? - ethylgona-2,5 (10) -diene-17 * -ol

In a mixture of 20 ml of dioxane, 20 ml of ether and 100 ml of liquid ammonia, 0.5 g of (±) 3 - methoxy -13 / 3- äthylgona -1,3,5 (10), 8 - tetraene-17λ-ο1 solved. The solution is cooled to -50 ⁰ C and treated with 1.2 g of metallic lithium is followed by stirring. After 30 minutes, 20 ml of ethanol are added dropwise to the reaction solution. The resulting solution is left to stand at room temperature to remove the ammonia. The residue is mixed with water and ether. The mixture is shaken out, whereupon the ether layer is separated. The ether layer is washed with water, dried and evaporated to remove the solvent, whereby 0.5 g of (±) 3-methoxy-13 £ -äthylgona-2,5 (10) -diene-17a-o! can be obtained as an orange oil.

7) (±) 3-Methoxy-13/3-ethylgona-1,5 (10) -dien-17-one

A solution of 0.2 g of (±) 3-methoxy-13 /? - ethylgona-2,5 (10) -diene-17 "-ol in 50 ml of toluene is concentrated to about 20 ml. The solution is mixed with 0.2 g of aluminum propoxide, whereupon the mixture is refluxed for 3 hours. The reaction solution is mixed with water and neutralized with dilute sulfuric acid and then subjected to steam distillation. The residue is extracted with ether. The ether layer is washed with water, dried and evaporated to remove the solvent, 0.1 g of (±) 3-methoxy-13 /? - äthylgona-2,5 (10) -dien-17-one being obtained. After recrystallization from ether and then from a mixture of ethyl acetate and hexane, crystals are obtained with a melting point of 158 to 16O ⁰ C.

Elemental analysis for C ₂₀ H ₂ SO ₂ :

Calculated ... C 80.00, H 9.33;
Found ... C 80.08, H 9.39.

Example 3

1) (±) 3-Methoxy-17 "-hydroxy-8,14-secoestral, 3,5 (10), 9-tetraen-14-one-17-hydrogen succinate

4 g of succinic anhydride are added to a solution of 2 g of (±) 3-methoxy-17a> hydroxy-8,14-secoöstra -1,3,5 (10), 9-tetraen-14-one in 15 ml of pyridine. The mixture is stirred at 75 to 80 ° C. for 20 minutes. After cooling, the reaction solution is mixed with water and then extracted with ether. The ether layer is washed with water, dried and evaporated to remove the solvent. A small amount of ethyl acetate is added to the residue, crystals being formed. After recrystallization from ethyl acetate, 2.1 g of (±) 3 - methoxy -17 * - hydroxy - 8.14 - secoöstra -1.3, 5 - (10), 9 - tetraen -14 - one -17 - hydrogen succinate with a melting point of 121 to 123 ^° C.

Elemental analysis for C ₂₃ H ₂₈ O ₂ :
Calculated ... C 68.98, H 7.04;
found. ... C 69.20, H 6.98.
Ultraviolet absorption: λ% £ ^nat 265 πιμ (ε = 20570) Infrared absorption: v ™ °, 1735, 1718 cm- ¹ .

2) quinine salt of (±) 3-methoxy-17 «-hydroxy-

8,14-secoöstra-1, 3,5 (10), 9-tetraen-14-one

17-hydrogen succinate

To a solution of 3 g (±) 3-methoxy-17 * -hydroxy-8,14-secoöstra-l, 3,5 (10), 9-tetraen-14-one-17-hydrogen succinate in 25 ml acetone is a Added a solution of 2.43 g of quinone in a mixture of 20 ml of acetone and 4 ml of methanol. The resulting solution is allowed to stand at about 5 ⁰ C, the quinine salt of (±) 3-methoxy-17a-hydroxy-8,14-secogonal, 3,5 (10), 9 - tetraene -14- on -17 - hydrogen succinate is precipitated. The precipitate is removed by nitration and recrystallized from a mixture of methanol and acetone, 2.1 g of crystals having a melting point of 170 to 171 ^° C. being obtained.

(λ)! ³ + 26 ° (C - 1.0, CHCl ₃ ). The mother liquor is concentrated to give 2.3 g of an oil. (*)! ³ + 118 ° (C = 1.0, CHCl ₃ ).

3) (-) 3-Methoxy-17; x-hydroxy-8,14-secoestral, 3,5 (10), 9-tetraen-14-one

2.2 g of the oil which was obtained in the manner described above under 2) and has the optical activity (/%) " + 118 ° is dissolved in 30 ml of chloroform. The solution is shaken with 20 ml of 10% sulfuric acid. The chloroform layer is separated and extracted twice with 10% sulfuric acid, the chloroform layer is washed with water, dried and evaporated to remove the solvent, the residue is dissolved in 20 ml of methanol and the solution is mixed with 14 ml of a 10N aqueous solution of Potassium hydroxide is added with ice while cooling, whereupon the mixture is stirred for 1 hour.

set of water, the reaction solution is extracted with ether. The ether layer is washed with water, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of methanol and water, 0.8 g of (-) 3-methoxy-17 «-hydroxy-8,14-secoöstra-l, 3,5 (10), 9-tetraene-14- on can be obtained in the form of needles with a melting point of 102 to 103 ^° C.

(λ)! ⁴ -83.6 ° (C = 1.0, CHCl _3).

From 1.4 g of the crystals produced according to Section 2 of this example, which have the optical activity (λ)! ³ + 26 °, 0.5 g (+) 3-methoxy-17 <x-hydroxy-, 8, 14-secoöstra-1, 3,5 (10), 9-tetraen-14 were in the manner described above -one obtained in the form of colorless needles melting at 102 to 104 ⁰ C, (α) !, ⁴ + 81.6 ° (C = 1, CHCI _3).

4) (-) 3-Methoxyestra-1,3,5 (10), 8,14-pentaen-17 "-ol

To a solution of 0.6 g of (-) 3-methoxy-17 <x-hydroxy - 8.14 - secoöstra - 1,3,5 (1O), 9 - tetraen -14 - one in 16 ml of methanol becomes 2.7 ml of concentrated hydrochloric acid given. The mixture is refluxed for 40 minutes with moderate stirring. The reaction

solution is poured into water and mixed with benzene extracted, whereupon the benzene layer is separated. The benzene layer is washed with water, dried and evaporated to remove the solvent, followed by standing at room temperature will. Here, crystals are precipitated, which are recrystallized from a small amount of methanol, where 0.55 g (-) 3 - Methoxyöstra - l, 3.5 (10), 8, 14-pentaen-i7a-ol as colorless needles with a melting point 63 to 64 ° C can be obtained. («)? -190 °.

From 0.45 g of (+) 3-methoxy-17a-hydroxy-8,14-secoöstra-1,3,5 (10), 9-te-; raen-14-one are obtained in the same way as described above , 0.4 g of (-j-) 3-Methoxyöstra-1,3,5 (10), 8,14-pentaen-17a-ol obtained in the form of crystals with a melting point of 63 to 64 ^c C («)? + 190.8 ° (C = 0.5, CHCl ₃ ).

5) (-) 3-Methoxyestra-1,3,5 (10), 8-tetra-17 * -ol

0.4 g of Raney nickel are added to a solution of 0.6 g of (-) 3-methoxyestral, 3.5 (10), 8,14-pentaen-17a-ol in 30 ml of dioxane. The mixture is shaken in the flowing hydrogen until 47 ml of hydrogen have been absorbed. The catalyst is then filtered off and the filtrate concentrated, crystals being formed. The crystals are recrystallized from ether, 0.5 g of (-) 3-methoxyestra-1,3,5 (iO), 8-tetraen-17 <x-ol as platelets with a melting point of 113 to 6 ° C being obtained. (, x) S * -31.5 ° (C = 1.0, CHCl ₃ ).

From 0.45 g of (+) 3-methoxyestra-1,3,5 (10), 8,14-pentaen-17 «-ol, in the same way as described above, 0.4 g (+ ■) 3 -Methoxyöstra-1,3,5 (10), 8-tetraen-17 «-ol obtained, (α)? ¹ + 41.3 ° (C = 1.0, CHCl ₃ ).

6) (+) 3-Methoxyestra-1,3,5 (10) -triene-17c \ -oI

In a mixture of 20 ml of dioxane, 40 ml of tetrahydrofuran and 250 ml of liquid ammonia, 0.4 g of (-) 3 - methoxyestra - 1,3,5 (10), 8 - tetraen-17, \ - ol are dissolved. 2 g of metallic potassium are added to the solution while cooling to -30 to -50 ° C. The mixture is then stirred for 2 hours. Ammonium chloride is added to the reaction solution to decompose the excess potassium. The reaction solution treated in this way is then left to stand at room temperature to completely remove the liquid ammonia. The residue is dissolved in water and the mixture extracted with benzene. The benzene layer is washed with water, dried and evaporated to remove the solvent. The solid residue is recrystallized from a mixture of water and ethanol, 0.35 g of (+) 3-methoxyestra-1,3,5 (10) -trione-17a-ol in the form of needles with a melting point of 96 to 100.degree can be obtained. {oc)% ¹ + 17.6 ° (C = 0.5, CHCl ₃ ).

From 0.4 g of (+) 3-methoxyestra-1,3,5 (10), 8-tetraen-17 «-ol, in the same way as described above, 0.33 g of (-) 3-methoxyestra-1 , 3,5 (10) -trien-17a-ol as crystals of melting point 96 to 99 ⁰ C. («)? -17.6 ° (C = 0.5, CHCl ₃ ).

7) (+) 3-Methoxyestra 1,3,5 (10) -trien-17-one

To a solution of 0.2 g of (+) 3-methoxyestral, 3,5 (10) -trien-17a-ol 0.25 ml of an aqueous solution which concentrated 26.72 g of chromic anhydride and 23 ml are gradually added to 20 ml of acetone Contains sulfuric acid per 100 ml, whereupon shaken

will. Methanol is added to the reaction solution to decompose the excess chromic acid. The solution obtained is diluted with water, whereupon crystals are precipitated, which are filtered off. The crystals are washed with water and recrystallized from ethanol, 0.2 g of (+) 3-methoxyestra-1,3,5 (10) -trien-17-one having a melting point of 165 to 168 ° C. being obtained. (*)? + 167 ° (C = 1, CHCl ₃ ). 0.3 g of (-) 3-Methoxyöstra-1,3,5 (10) -trien-17 * -ol ίο becomes 0.25 g of (-) 3-Methoxyöstra-l in the same way as described above , 3,5 (10) -trien-17-one with a melting point of 162 to 168 ⁰ C (0? -147.6 ° (C = 1, CHCl ₃ ).

Example 4

3-methoxy-9,14-secoestra-1,3,5 (10), 9-tetraene-14,17-dione

In a solution containing 20 ml of dimethyl sulfoxide, 7 g of dicyclohexylcarbodiimide, 9.6 ml of pyridine, 0.48 ml Contains trifluoroacetic acid and 18 ml of benzene, 3.6 g of (+) 3-methoxy-17α-hydroxy-8,14-secoöstra-l, 3, 5 (10), 9-tetraen-14-one dissolved. The resulting solution is left to stand at room temperature overnight. After adding ether to the reaction solution, the resulting solution is mixed with a methanol solution of oxalic acid offset. The mixed solution is allowed to stand until the bubbling stops.

The solution obtained is mixed with water, whereby dicyclohexylurea is precipitated, which is filtered off. The ether layer is washed with water and evaporated to remove the solvent. The oily residue is chromatographed on a column filled with silica gel. From the eluate obtained with a mixture of benzene and ether, 3 g of 3-methoxy-8,14-secoöstra-l, 3,5 (10), 9-tetraene-14,17-dione of melting point 78 C ⁰ severed.

Example 5

1) 1-methoxyacetate of (±) 3-methoxy-17 <x-hydroxy-8,14-secoestra-1,3,5 (10), 8-tetraen-14-one

To a mixture of 0.4 g of (±) 3-methoxy-17 «-hydroxy-8,14-secoöstra-1, 3,5 (10), 9 - (11) - tetraen-14-one in a mixture of 0.13 ml of pyridine and 1.5 ml of dioxane are added to 0.37 g of 1-methoxyacetyl chloride. The whole mixture is left to stand overnight at room temperature. The reaction solution is mixed with water and then extracted with ether. The ether layer is washed with water, dried and evaporated to remove the solvent. The residue is chromatographed on a column filled with 20 g of silica gel. From the eluate obtained with a mixture of benzene and ether (4: 1) 0.7 g of 1-methoxyacetate of (±) 3 - methoxy-17a-hydroxy - 8.14 - secoöstra -1,3,5-

(10), 8-tetraen-14-one obtained as a colorless oil.

The Menthoxyacetat is dissolved in hot methanol and the solution cooled to -40 ⁰ C., whereupon an oil separates out, which by multiple repetition of dissolution in hot methanol and down

cooling is cleaned. The colorless oil thus obtained is left to stand with cooling, whereupon crystals separate out. The crystals will be out Recrystallized methanol, 0.12 g of 1-menthoxy

acetate of (+) 3-methoxy-17'-hydroxy-8,14-secoöstra-1,3,5 (10), 8-tetraen-14-one with a melting point of 88 to 90 ° C can be obtained. («) S * - 3 ° (C = 0.5, CHCl ₃ ). The combined mother liquor is concentrated, with 0.4 g of 1-menthoxyacetate of (-) 3-methoxy-17a-hydroxy-8,14-secoöstra-1,3,5 (10) 8-tetraen-14-one as a colorless oil can be obtained. («)? -50.3 (C = 0.5, CnCl ₃ ).

2) 3-methoxy-17 "-hydroxy-8,14-secoestral, 3,5 (10), 8-tetraen-14-one

To a solution of 0.1 g of 1-menthoxyacetate of (+) 3-methoxy-17a-hydroxy-8,14-secoöstra-1,3,5- (10), 8-tetraen-14-one in 5 ml of ethanol 1 ml of a 1 N potassium hydroxide solution in ethanol. The mixture is then stirred for 20 minutes at room temperature. Water is added to the reaction solution and the resulting solution is extracted with ether. The ethereal layer is washed with water, dried and evaporated to remove the solvent, 0.07 g of (+) 3-methoxy-17 «-hydroxy-8,14-secoöstra-1,3,5- (10), 8-tetraen-14-one is obtained as a pale yellowish oil.
(«) S ⁵ + 48 ° (C = 1.0, CHCl ₃ )

Infrared absorption: ν ™haben car *, 3500 (OH), 1730 (C = O), 1605, 1568, 1490 (aromatic ring).

From 0.3 g of 1-menthoxyacetate of (-) 3-methoxy-17 "-hydroxy-8,14-secoestra-1,3,5 (10), 8-tetraen-14-one 0.15 g of (-) 3-methoxy-17'-hydroxy-8,14-secoestra-1,3,5 (10), 9-tetraen-14-one is obtained in the same manner as described above. («)? -48MC - 1.0,

Infrared absorption: ν ™ _χ ^α3 cm- ¹ : 3500 (OH), 1730 (C = O), 1605,1568,1485 (aromatic ring)

3) (-) 3-Methoxyöstra-1,3,5 (10), 8,14-pentaen-

^{17a '01}

The (-) 3-methoxy-17'-hydroxy-8,14-secoestra-1,3,5 (10), 9-tetraen-14-one obtained is in the manner described in Example 3 (4) in (-) 3-Methoxyöstra-1,3,5 (10), 8,14-pentaen-17 «-ol converted.

4) 3-methoxy-8,14-secoostra-l ₅ 3.5 (10), 9-tetraene-14,17-dione

To a solution of 0.05 g of (+) 3-methoxy-17 «-hydroxy-8,14-secoöstra-1,3,5 (10), 9-tetraen-14-one 1 ml of an aqueous solution which concentrated 26.72 g of chromic anhydride and 23 ml is added to 5 ml of acetone Contains sulfuric acid per 100 ml, whereupon shaken will. The reaction solution is extracted with ether. The ether layer is washed with an aqueous solution of sodium hydrogen carbonate and then with water, dried and concentrated to remove the solvent, leaving 0.045 g (±) 3-methoxy-8.14 - secoöstra - l, 3.5 (10), 9 - tetraene -14.17 - dione can be obtained.

B e i s ρ i e 1 6

1) (-) nac-Acetoxy-S-methoxy-g.l ^ secoöstra-13 5 (10) 9-tetraen-14-ol

2.4 g of (-) 17-acetoxy-3-methoxy-8,14-secoöstra-1, 3,5 (10), 9-tetraen-14-one ([«lo ⁵ - 71 °) solved. To the solution 0.3 g of sodium borohydrate are added while cooling to -20 ⁰ C, followed by 1.5 hours stirred. The reaction solution is mixed with water and extracted with ether.

here. The ether layer is washed with water, dried and concentrated, with 2.4 g of (-) 17 "-acetoxy-3-methoxy-8,14-secoestra-1,3,5 (10), 9-tetraen-14-ol can be obtained as a colorless oil. (a) S ^e -11.1 ° (C = 1, chloroform)

i _n f _rarotab sorption: ν ££ cm- ': 3450 (OH), 1730
_{(Ester)>1605> im M95 (aromatic ring} j _ng)

2) (-) 17 <x -acetoxy-3-methoxy-9,14-exido-8,14-secoestra l, 3.5 (10) -triene

A solution of 2.4 g of (-) 17a-acetoxy-3-methoxy-8,14-secoöstra-l, 3,5 (10), 9-tetraen-14-ol in 100 ml of benzene is concentrated to 10 ml. Furthermore, a solution of 0.1 g of p-toluenesulfonic acid in 100 ml of benzene is concentrated to 10 ml. The two solutions are combined and left to stand at room temperature for 30 minutes. The reaction solution is shaken with an aqueous sodium hydrogen carbonate solution, whereupon the benzene layer is separated. The benzene layer is washed with water, dried and concentrated under reduced pressure to remove the solvent. The residue is chromatographed on a column filled with silica gel

* ⁵ cleaned. From the benzene eluate, 2.3 g (-, 17 «-

yy..A
(10) -triene obtained as a colorless oil. («)! * -20.8 ° (C = 1, chloroform).

i _n f _raro tabsorption:
_F by _cm -

r! 16 ¹ O 1575 1500

Ultraviolet Absorption:

χ au «« «277 πιμ (ε = 1820), 283 ma (ε = 1720)

3) (-) 3-Methoxy-9,14-oxido-8,14-secoestral, 3,5 (10) -trien-17-ol

To a solution of 2.3 g of (-) 17 ″ -Acetoxy-3-methoxy-9,14-oxido-8,14-secoöstra-l, 3,5 (10) -triene in 30 ml of ethanol, 20 ml of a In potassium hydroxide solution in ethanol, whereupon the mixture is stirred for 1 hour at room temperature. The reaction solution is mixed with water and the mixture with ether extra _{mert The ether layer winl} ^ _{1 water washed>} dried and concentrated to remove the solvent, 1.9 g of (-) 3-methoxy-9,14-oxido-8,14 -secoöstra-l, 3,5 (10) -trien-17-ol can be obtained as a colorless oil.

^ _cm _
_ma tenring)

_(QH)

_{4) (+)} see Methoxv-g. ^ Oxido-SU-secoöstra-
^ ₁₇ '

n-i / -on

l

A solution of 1.9 g of (-) 3-methoxy-9,14-oxido-8,14-secoöstra-1,3,5 (10) -triene-17 is added to a solution of 2 g of chromic anhydride in 30 ml of pyridine -ol in 10 ml of pyridine, whereupon the mixture is stirred for 30 minutes at room temperature. The reaction solution is ^{poured into water} and the mixture is extracted with ether. The ether layer is washed with dilute sulfuric acid, with an aqueous solution of sodium hydrogen carbonate and then with water, dried and concentrated, whereby 1.65 g of (-r-) 3-methoxy-9,14-secoöstra-l, 3.5 (10 ) -trien-17-one can be obtained as a residue, which is then purified by chromatography, whereby crystals from

If

23 I 24

Melting point 77 to 80 ⁰ C can be obtained, (λ)? traen-14-one in a mixture of 5 ml of pyridine and 5 ml

+ 35 ° (C = 1, chloroform). Water becomes 0.1 g of sodium borohydride with cooling

Infrared absorption: fi ^f ^ ^{0 bis} . ⁰ T ^ ⁸ T ^ followed by stirring. To

v ™ ⁰¹ cm- ¹ : 1734 (Oxorest), 1615, 1580, 1500 (Aro- ¹ hour, the reaction solution is mixed with water

matenring) ' ^v 5 and the mixture with hydrochloric acid to about pH 5

Ultraviolet absorption: adjusted and then extracted with ether. the

Ä " ⁰¹ 276 ιημ (e = 1870), 283 ηιμ (ε = 1740). The layer of ethene is washed with water and dried

and concentrated, with (+) 17 «-hydrogen succinoyloxy-

cw, μ »* -ι. · ■. ii cmo λλ ι 3-methoxy-8,14-secoöstra-l, 3,5 (10), 9-tetraen-14-ol

5) (+) 3-Methoxyostra-l, 3,5 (10), 8,14-pentaen- _{lo obtain w} i _rd

17a-ol

To a solution of 1.4 g of (+) 3-methoxy-9,14-oxi- ² ) (+> 3-methoxy-9,14-oxido-8 14-secoöstra-

do-8,14-secoöstra-1,3,5 (10) -trien-17-one in 30 ml mel, 3,5 (10) -tnen-17-ol

ethanol are given 5 ml of concentrated hydrochloric acid, the compound obtained according to Example 3 (1) er

whereupon the mixture is refluxed for 30 minutes. 15 indicates that described in Example 6 (2) and (3)

Reaction solution is mixed with water and the way 1 g of (+) 3-methoxy-9,14-oxido-8,14-secoöstra-

Mixture extracted with ether. The ether layer becomes 1,3,5 (10) -trien-17-ol.

with an aqueous solution of sodium hydrogen, w>■>., _tU η λ λ -λ ο λ λ

carbonate and washed with water, dried and ³ > (~) B-MethoxyW-oxido-S ^ secoostra-

concentrated to remove the solvent. From ao l, 3.5 (10) -ton-17-one

1.2 g of (+) 3-methoxyöstra- 0.8 g of (-) 3-methoxy-9,14-oxido-8,14-secoöstra-

1,3,5 (10), 8,14-pentaen-17 «-one in the form of crystals 1,3,5 (10) -trien-17-one are applied to those in Example 6

obtained from melting point 60 to 66 ⁰ C, (λ)? ¹ + 194 ° (4) from the manner described in Examples (2)

(C = 1, chloroform). obtained connection formed. («)? -35 ° (C = 1,

Infrared absorption: »5 chloroform).

"SS" cm- ¹ : 3400 (O) 4) (-) 3-Methoxyöstra-1,3,5 (10), 8,14-pentaen-

Ultraviolet absorption: 17 "-ol

λ * £ ^ano1 311 ΐημ (ε = 24000). The compound obtained according to Example 8 (3)

30 gives 0.8 g in the manner described in Example 6 (5)

Example 7 (-) 3-Methoxyestra-1,3,5 (10), 8,14-pentaen-17 (x-ol as

^ _r .. _Λ,. ,.,, ... .. oil that is recrystallized from methanol, with Na-

1 ^ uTl J? ⁵ "" ^{8 FROM} VSV ^? ⁰ ; ^{dels with a} melting point of 63 to 64 ° C can be obtained.

13-ethyl-8,14-secogona-1,3,5 (10) -tnen-17-one in 40 ml

Methanol, 10 ml of concentrated hydrochloric acid are

give, whereupon the mixture is refluxed for 1 hour. the

Reaction solution is mixed with water and that

Mixture extracted with ether. The ether layer is Example 9

with an aqueous solution of sodium hydrogen

carbonate and then washed with water, dried (+) 3-Methoxyöstra-2,5 (10) -dien-17-one

and concentrated to remove the solvent, ⁴ ° _{D gm id} 3 _{(5) obtained (} _ _{} 3rd methoxy} .

Si ^tW ^ ¹ ^ ^(±) ^^ ^et ίί ^{^ Xy} ; ¹ ^ ^athylε H ^na ■ ¹ ' ³ ' ⁵ "ö _S tra-l, 3,5 (10), 8-teiraen-17« -ol is based on the in the by-

as oil received w.rd. ^ j ₍₆ ) described manner in (+) 3-Methoxyöstra-

; Ultraviolet absorption: λ ££ ■ ""> '310 mμ (ε = 24000). 2,5 (10) -dien-17a-ol converted. The thus obtained

j 45 dienol is based on that described in Example 1 (7-1)

\ Examples manner in (+) 3-Methoxyöstra-2,5 (10) -dien-17-one from

{iw, χ, ·, it j ·· λ ι. Melting point 123 to 126 ⁰ C further converted.
1) (+) na-hydrogen succinoyloxy-S-methoxy-

j 8,14-secoöstra-l, 3,5 (10), 9-tetraen-14-ol Infrared absorption:

To a solution of 2.2 g (+) 17o> Hydrogen- 50 ν ^ '°' 1740 cm- ¹ (carbonyl residue)

succinoyIoxy-3-methoxy-8,14-secoestra-1,3,5 (10), 9th-1700,1667 cm- ¹ (double bond).

1 sheet of drawings

Claims (3)

Patent claims: 1. Process for the production of 13 /? - koh.'enwasserstoffubstituierten Gona - 1,3,5 (10) - trien-17-ones, thereby characterized in that one according to methods known per se (a) a 13/5 lower alkyl, phenyl or benzyl substituted one 8,14-secogona-1,3,5 (10), 9-tetraene-14,17-dione reduced with a metal complex, (b) the compound obtained in this way into a 13 /? - lower-alkyl-, -phenyl- or -benzyl-substituted 17'-hydroxy-8,14-secogona-1,3,5- (10), 9-tetraen-14-one and. an ent-13/5-lower alkyl, -phenyl- or -benzyl-substituted 17 "- hydroxy - 8,14 - secogona - 1,3,5 (1O), 9 - tetraen-14-one separates, (c) the 13/3 lower alkyl, phenyl or benzyl substituted one 17 <x-Hydroxy-8,14-secogona-1, 3, 5 (10), 9-tetraen-14-one in the presence of an acidic Cyclodehydrated catalyst, (d) the obtained 13 /? - lower-alkyl-, -phenyl- or -benzyl-substituted gona-1,3,5 (10), 8,14-pentaen-17a-ol brings into contact with hydrogen in the presence of a reducing catalyst, (e) the obtained 13 / J-lower-alkyl-, -phenyl- or -benzyl-substituted gona-1,3,5 (10), 8-tetraen-17a-ol reacts with alkali metal in liquid ammonia and (f) the 13/9 lower alkyl, phenyl or benzyl substituted one Gona-1,3,5 (10) -triene-17 »-ol oxidized. 2. The method according to claim 1, characterized in that according to step (b) of claim 1 obtained ent-13 / f-lower-alkyl-, -phenyl- or -benzyl-substituted 17 <x -hydroxy-8,14-secogona-1,3,5 (10), 9-tetraen-14-one to a 13/3 lower alkyl, -phenyl- or -benzyl-substituted 8,14-secogona-1,3,5 (10), 9-tetraene-14,17-dione oxidized and then performing steps (a) to (f). 3. The method according to claim 1, characterized in that one