DE1643618C3 - Process for the preparation of 13-beta-alkyl-3,11,17,20,21-pentaoxylated-18,19-dinorpregnenes and 13-alkyl-11 -oxylated-18,19-dinorpregnanes - Google Patents

Description

wherein R ^{1 is} an n-alkyl group having 1 to 3 carbon atoms, the radicals R ² and R ³ together form an ethylidene group, W is an oxo or protected oxo group or a * - or / 3-hydroxy or protected hydroxy group and Y is a Hydroxy or protected hydroxy group, in which case the ring A is aromatic or an etherified hydroxy group and the ring A contains a 2,5 (10) -diene system or Y is a protected oxo group with the simultaneous presence of a double bond in the 4 -, 5 (6) - or 5 (1O) -position, with or without a second double bond in the 2- or 3-position, or a; Oxo group in which rings A and B have a double bond in the 4-, 5 (10) or 5 (6) positions, characterized in that a 13-alkyl obtainable according to claim 2b) is obtained by methods known per se - 3 - oxylated -11 - protected - hydroxy-18,19-dinorpregnen-17-ol is dehydrated and, if desired, then the reactions according to claim 2d) are carried out.

4. Process for the preparation of a 13-alkylll-oxylated-18,19-dinorpregnane the general formula

50

55

where R ^{1 is} an n-alkyl group with 1 to 3 carbon atoms, R ^{2 is} a hydroxyl or protected hydroxyl group, W and X are λ- or /? - hydroxyl or protected hydroxyl or oxo or protected oxo groups, Y is a hydroxyl or protected hydroxyl group, in which case ring A is aromatic, or a protected oxo group, in which case rings A and B have a double bond in the 4-, 5 (10) or 5 (6) -position with or without an additional double

This invention relates to methods of manufacture

dinorpregnenen with pharmacological effectiveness z. B. corticosteroids and other hormonal effects, especially of 13/3-ethyl-18,19-dinorpregn-4-en-17 *, 21-diol-3, ll, 20-trione- (18-homo-19-norcortisone) and 13 /? - ethyl-18,19-dinurpregn-4-en-ll / S, -17 », 21-triol-3,20-dione- (18-homo -19- norcortisol). The invention also relates to methods of production of 13-alkyl-11-oxylated-18,19-dinorpregnanes.

To describe the invention reference is made to the drawings, wherein

F i g. 1 the preparation of a 13-alkyl-III * or / S-acyloxy or -hydroxy-18,19-dinorpregna-4,17 (20) -diene or -l, 3,5 (10), 17 (20) -tetraens and their conversion to 4-en-3-ones explained,

F i g. 2 the conversion of the compounds of FIG. 1 to a 13-alkyl-l 1 / 3,17a-dihydroxy-18,19-dinorpregn-4-en-3,20-dione explained

F i g. 3 and 4 show the conversion of a compound of FIG. 2 to IS-homo-W-norcortisol and 18-homo-19-norcortisone and

F i g. 5, 6 and 7 are optional conversions of the compounds of FIG. 1 to explain these connections.

The aforementioned compounds are difficult to prepare by total synthesis for the following reasons:

(1) They have a number of functional groups, some of which must be protected while some of the other functional groups are to be modified.

(2) The side chain in position 17 has particularly ir stereochemically complex in nature and therefore their structure poses considerable problems

(3) There is a risk of epimerization at the 9-position if the oxylated function is in the 11-position ment should be introduced, especially in those compounds in which the ring A is aromatic

(4) The compounds are chemically so granular and so different from the easily available ones! Total synthesis steroids that their synthesis inevitably fell through a large number of stages resulting problem of the steadily decreasing Ge total yields.

It is the aim of the invention to provide a sequence of procedural steps through which the prior compounds mentioned can be produced

The invention provides a process for the preparation of 13 /? - AlkylAl U7,20, ^ l-pentaoxylated-ie, 19-dinorpregnenes the general formula

■ w - '

wherein R ^{1 is} an n-alkyl group with 1 to 3 carbon atoms, X is a β - [(2'- hydroxy or protected hydroxy -) -! '- hydroxy, protected hydroxy, oxo or protected oxo -) - ethyl ] - * - (hydroxy or protected hydroAy -) - methylene group, W is a «- or ^ -hydroxy or protected -hydroxy group or an oxo or protected oxo group,

Y is a hydroxyl group or a protected hydroxyl group is, and the ring A is aromatic or, if

Y is an ether group, ring A is the 2,5 (10) -diene system contains, or Y represents an oxo group and rings A and B have a double bond in the 4 (5) - or 5 (10) -position, or Y is a protected oxo group and rings A and B are Double bond in the 4 (5) -, 5 (10) or 5 (6) position, with or without a second double bond in the 2 (3) - or 3 (4) position, characterized in that one according to methods known per se

(a) a 13 /? - alkyl-3-hydroxy- or protected -hydroxy -17f - ethylgona -1,3,5 (10), 9 (11) -tetraene -17f - oil in the II-position to a 13 /? - alkyl-17f-ethyIgona-1,3,5 (10) -triene-ll, l7f-diol hydroborated,

(b) the 11-hydroxy function produced in 13/9-alkyl-17f-äthylgona-l, 3.5 (10) -triene-ll, 17f-diol by converting to 11-oxo group, 11-protected oxo group or by a known method protects an 11-protected hydroxy group,

(c) the 17-hydroxy function of the 11-oxo, protected -Oxo- or protected hydroxy-13 /? - alkyl-17 £ -äthylgona-1,3,5 (10) -trien-17f-ols dehydrated to form a corresponding 17-ethylidene compound and optionally the protective group removed from the 11-oxo or 11-hydroxy group,

(d) the 3-alkoxy-1,3,5 (10) -trirn is reduced to form a 3-alkoxy-2,5 (10) -diene according to Birch,

(e) the product obtained from the Birch reduction is hydrolyzed to form a 5 (10) -En-3-one or 4-en-3-one,

(f) the 17-ethylidene group at the 17, 20 and 21 positions to form a 17,20,21-trioxygenated one Oxidized derivatives, steps (a) to (c) in the order given above and the Steps (d) through (f), of which (d) and (e) are optional steps to be carried out, in any suitable one Sequence can be carried out, with steps (d) and (e), if desired, / wiping out the different Oxidation stages are carried out in stage (f) and if desired, one or more of the subsequent reaction steps are carried out in any suitable stage using methods that are also known per se:

(I) Oxidation of an 11-hydroxy group to one 11-oxo group,

(II) reduction of an 11-oxo group to a 1 \ ß-H \ - droxy group,

(III) coalizing or converting a 3-oxo group into an enol ether or enol ester group,

(IV) converting an 11-hydroxy or 11-oxo group into an esterified 11-hydroxy or a ketalized one 11-oxo group,

(V) converting a 17 or 21 hydroxy group c into an esterified hydroxyl group,

(VI) Converting a 20-oxo group to a ketalized one 20-oxo group or

(VII) Isomerizing with an acid or a base of a 5 (10) -En-3-one to a 4-en-3-one or

(VIII) Forming a 3-alkoxy group from a 3-hydroxy group or from a 3-protected hydroxy group, different from a 3-alkoxy group.

The invention also relates to a method for production of a D-alkyl-II-oxylated-IS ^ -dinorpregnans the general formula

wherein R ^{1 is} an n-alkyl group having 1 to 3 carbon atoms, R ^{1 is} a hydroxy or protected hydroxy group and R ^{3 is} an ethyl group or the radicals R ² and R ³ together form an ethylidene group, W is an oxo or protected oxo or a -x- or / 3-hydroxyl or protected hydroxyl group and Y is a hydroxyl or protected hydroxyl group, in which case the ring A is aromatic or an etherified hydroxyl group and the ring A is a 2,5 (1O) -diene- System contains or Y is a protected oxo group with the simultaneous presence of a double bond in the 4-, 5 (6) or 5 (10) -position, with or without a second double bond in the 2- or 3-position, or is an oxo group , in which the rings A and B have a double bond in the 4-, 5 (10) or 5 (6) positions, characterized in that one according to methods known per se

(A) a 13-alkyl-3-hydroxy- or protected -hydroxy-17f-äthylgona-1,3,5 (10), 9 (II) -tetraen-17f-ol hydroborated in the ll-position,

(b) protects the 11-oxygen function formed and, if desired,

(c) the 17-hydrox> function dehydrates under Formation of an ethylidein group and in turn,

(d) if desired, the Ila -hydroxygruppc (after Removal of the protecting group) to a 11/9 hydroxy group epimerized or a 1 III hydroxy group oxidized to an 11-oxo group, the obtained Subjecting the compound to a Birch reduction and hydrolysis, the 3-Kclone obtained is converted into a protected 3-Kcton transferred or the 11-hydroxy function again protects.

The invention also relates to a method for producing an IS-alkyl-II-oxylated ISL ^ dinoriregnans the general formula

IO

in which R ^{1 is} an n-alkyl group with 1 to 3 carbon atoms, the radicals R * and R ³ ™haben ^η ., ^ε ' ^η . ^{Form ε} _ε ethylidene group, W is an oxo or protected oxo group or a «- or ^ -hydroxy or protected hydroxyl group and Y is a hydroxyl or protected hydroxyl group, where in this case the ring A is aromatic or an etherified hydroxyl group and the ring A contains a 2,5 (10) -D.en-system or Y is a protected oxo group with the simultaneous presence of a double bond in the 4-5 (6) - or 5 (10) -position, with or without a second one Double bond in the 2- or 3-position, or an oxo group in which the rings A and B have a double bond in the 4-, 5 (10) or 5 (6) positions, characterized in that after an known methods a 13-alkyl-3-oxylated-II -protected- 3 <> hydroxy-18,19-dinorpregnen-17-ol obtainable according to claim 2 b) is dehydrated and, if desired, then carries out the reactions according to claim 2d).

Finally, the invention relates to a process for the preparation of an n-alkyl-11-oxylated-IS ^ -dmorprcgnans of the general formula 17-ethylidene intermediate after removing the protective group of a II <x -protected hydroxyl group is epimerized to a 11/3 hydroxyl group, for example by oxidation to an 11-oxo group and by reducing the latter to a 11/3 hydroxy group and then carrying out the following reaction steps:

(i) Birch reduction and hydrolysis of the Birch reduction product, Oxidation at the 17 and 20 positions and oxidation at the 21 position or

(ii) Oxidation at the 17 and 20 positions, Birch reduction and hydrolysis of the Birch reduction products, 21-oxidation or

(iii) Oxidation at the 17 and 20 positions, oxidation at the 21 position, protection of the 20-oxo group, then Birch reduction and hydrolysis of the Birch reduction product and removal of the protective group, in each case with formation of a 13-alkyl-18,19-dinorcortisol.

(2) Process in which the in the dehydrati-, ie ^ tufeerMtenen-Äthylideii-Z ^ henptodutt. fSs desired after removing any 11-schutinden Groups at the 17 and 20 positions oxidize Sri and then the subsequent reaction stages be performed:

(i) Birch reduction and hydrolysis of the product, O! dation at the 21-position and Ep.mens ^ ung a ll * -hydroxy group to a ^ reich-reduction and hydrolysis of the product, omerization of a ll "-hydroxy group to a U ₁ J Hydroxy group and oxidation at the 21-position

₄ o (ii.) Epimerization of a 11, -hydroxy group to an H ^ hydroxy group, Birch reduction and hydrolysis of the product and oxidation at the 21-position, or ^ ₂₁ . _{Ste "ung Epimc} ization

•, 11 "hydroxy group to form an 11/3 hydroxy-Xpe BiAdXon ^ nd hydrolysis of the product ^ Protecting the 20-oxo group and removing the

where R ^{1 is} an n-alkyl group with 1 to 3 carbon atoms, R "is a hydroxy or protected hydroxy group, W and X are α- or / 3-hydroxy or protected hydroxy or oxo or protected oxo 5« groups, Y is a hydroxyl or protected hydroxyl group, in which case ring A is aromatic, or a protected oxo group, in which case rings A and B have a double bond in the 4-, 5 (10) or 5 (6) Position with or without an additional double bond in the 2- or 3-position, or an oxo group, in which in this case the rings A and B contain a double bond in the 4-, 5 (10) or 5-positions , characterized in that a U-alkyl-3, ll-dioxylated-18,19-dinorpregn-17 (20) -en obtainable according to claim 1 e) is obtained by methods known per se

further unsaturation in ring A is oxidized at the 17 and 20 positions. _6s

Explanations are:

(1) A method in which an IH-hydroxy group c of the n ^ hydroxyl group obtained in the dehydration step Oxidation at the 21st

SS KSKd hydrolysis of the product infer protecting the 20-oxo group and removing de.

of the product (protecting the epimerization of an Ila -hydroxy group into one 11/3 hydroxy group and removing the 20-protect the group, in each case with the formation of an IS-alkyl-IS.W-dinorcortisols.

(3) Process in which the 17-ethylidene intermediate product obtained in the dehydration sierungsslufe if desired, after hydrolysis of the 11-protecting group, Birch reduction and hydrolysis de Product is subjected and then the subsequent reaction stages are carried out:

(i) Oxidation at the 17 and 20 positions, oxidation at the 21 position, and epimerization one 11 "-hydroxy group to a 110-hydroxy group. (while protecting the 20-oxo group and removing d <

protective group), or

609 615/5 ^

(ii) Oxidation at the 17 and 20 positions, epimerization an Ila-hydroxy group to a 110-hydroxy group and oxidation at the 21-position, or

(iii) Epimerizing a II «-hydroxy group to a 11 / J-hydroxy group, oxidation at the 17- and 20 positions and oxidation at the 21 position, in each case with formation of a 13-alkyl-18,19-dinorcortisol.

The hydroboration stage

In this description, the term "hydroboration" is explained as a two-stage process in which a compound containing a double bond with a borohydride such as diborane or an alkyl borane is reacted to form a steroid boron compound, which is then reacted with an oxidizing agent, such as alkaline hydrogen peroxide, to remove the boron residue and introduce a Hydroxy group is treated. The introduction of the hydroxy group and the hydrogen atom into the Steroid molecules are generally cis addition and the addition is usually trans to the substituent in the 13-position. Hence when the hydroboration process is carried out on a Gona-1,3,5 (10), 9 (II) tetraene, a Compound obtained in which a -hydroxy group in the 11-position and an H-WaSSCrStOrT in the 9-position is available.

The hydroboration reaction is preferably, but not necessarily, carried out on compounds which do not contain any active hydrogen atoms which, in the event of their presence, form part of the diborane would destroy (but would return to the original group in reconditioning). In addition, the alkaline peroxide reaction of the organoborane would be converted into an alcohol by an activated one or acidic hydrogen atom are affected. For these reasons it is preferred any 3-hydroxy group protected, e.g. B. by esterification. The 17-hydroxy group can, however, like shown in Example 1, do not intervene in a very disruptive manner. Those associated with an aromatic ring Alkoxy (ether) groups remain unaffected by the hydroboration, while the ester (acyloxy) groups normally be reduced to the parent hydroxy group. There can be a multitude of ether groups be present, e.g. B. cyclopentyloxy and cyclohexyloxy groups. Carbonyl groups are im generally reduced to hydroxyl groups in the hydroboration reaction.

To explain the hydroboration process, the compound to be hydrobored is dissolved in dry tetrahydrofuran and treated with excess diborane, which by adding a solution of sodium borohydride in diglyme to a solution of boron trifluoride etherate in diglyme would. The reaction mixture is brought to room temperature over a period of several hours and then water was added to decompose the excess diborane. It will Hydrogen peroxide and aqueous sodium hydroxide added and the mixture on for half an hour Heated to reflux. After evaporation of the solvent, the product is made by conventional acid-base extraction and recrystallization process isolated.

Suitable solvents for the hydroboration reaction are ethers, for example tetrahydrofuran, Diethyl ether and diglyme (the dimethyl ether of diethylene glycol).

The diborane reactant may or may not be introduced into the reaction vessel with a gas inlet tube it can be formed in situ.

The latter optional method is carried out using one of the alkali metal borohydrides or Aluminum hydride together with a reagent such as ίο aluminum trichloride, boron trichloride or boron trifluoride causes, as described in H. C. B rο w n. "Hydroboration" (1962), published by Benjamin. A preferred combination consists of sodium borohydride and boron trifluoride etherate, dissolved in diglyme.

For illustration, compounds of the general formula

wherein R ^{1 is} an n-alkyl group having 1 to 3 carbon atoms and W is an oxo or protected oxo group or a hydroxyl or protected hydroxyl group, R ^{2 is} a hydroxyl or protected hydroxyl group, R ^{3 is} an ethyl group and Y is a hydroxyl or protected hydroxyl group , by hydroborating a compound of the general formula

in which the radicals R ¹ , R ² , R ³ and Y have the meaning given above, are prepared to introduce an Ila -hydroxy group and then, if the group Y, W and R ^{2 is} not a desired group, this can be subsequently carried out by a appropriate procedures are formed.

The starting materials for the hydroboration procedures can be produced according to the procedure described in the description of the britishei Patent 10 41 277 is described. For example, 13/3, 17Ä-diethyl-3-methoxygona-1,3,5 (10), 9 (ll) -tetraen-17 /? -Ol from the corresponding 17 “-ethi nyl compound by catalytic hydrogenation ii Presence of a partially poisoned catalyst z. B. Pailadium on calcium carbonate catalyst, de is partially poisoned with pyridine

Protection of the hydroxyl group

At this stage the formed ll <* - oxygen function protected to keep you dehydrated

3-methoxy-13 / ?, 17. <x-diethylgona-l, 3,5 (10) -triene-

3-methoxy -13 / 3.17a - diethyl -11 "- acet-oxygonal, 3.5 (10) -triene-1 7 / S-ol.

A particularly useful compound is 3-methoxy-130,17a-diethylgona-1,3,5 (10) -triene-lla, 17/3-diol, because these and other compounds like this are selectively esterified (for example acetylated) can, for the preparation of the corresponding II * -acyloxy-17/9-hydroxy compound. This reaction can be carried out in the presence of a carboxylic acid anhydride (e.g. acetic anhydride) and a base (e.g. Pyridine).

An embodiment of the above method can be explained as a method in which a connection the general formula

R ¹ OH

wherein R ¹ and Y have the meanings given above and W is a λ or /? - hydroxyl group, is selectively protected to form the corresponding compound, wherein W is a protected hydroxyl group.

Dehydration process

Suitable reactants for the dehydration process are thionyl chloride in pyridine, Phosphorus oxychloride, p-toluenesulfonic acid or strong ones

to prevent the subsequent dehydration process. Protection can be done both through conversion to a protected hydroxy group as well as by conversion to an oxo or protected Oxo group take place. ;

For example, they can be an IIIa hydroxyl group containing Hydroborieruragsprodukte be esterified or etherified with the formation of the corresponding Ester or ether. Optionally, the 11 ^ hydroxy groups containing compounds under suitable κ conditions (for example essentially neutral Oxidation conditions such as B. pyridine and chromium trioxide) to form the corresponding 11-oxo compound oxidized, which can then be ketalized or reduced; if the reduction with borohydrides or lithium aluminum hydride is carried out, the product becomes mainly the 11 / S-hydroxy compound thereby making the 11/3 hydroxy series of steroids and their derivatives accessible will. It is preferred that the hydroxy group ao in the 17 / S position be protected from reduction, for example through etherification. After such a reduction, the 11/3 hydroxy group becomes, for example by esterification, protected.

Useful compounds obtained by hydroboration processes and the post processes described above can be produced are:

Acids, for example sulfuric acid and perchloric acid.
So can the compounds of the general formula

wherein R ¹ and Y have the meanings given above, and W is an oxo or a protected oxo group, or a hydroxy or a protected hydroxy group, by dehydrating a compound of the general formula

R ¹ OH

30 are prepared, in which Y and R ^{1 have} the meaning given above and W is a «- or β-protected hydroxy, oxo or protected oxo group and, if the group Y or W is not the desired, this can then be replaced by a suitable Post-process are formed.

A particularly useful starting material for the dehydration process is a compound in which W is an acyloxy group, because these compounds can be easily obtained by the selective acylation process described above. It is generally convenient to carry out the dehydration reaction on a compound in which W is an acyloxy group such as acetoxy, although compounds in which W is oxo, protected oxo, or one of the other protected hydroxy groups can also be used . Additionally, the temperature should be carefully controlled in the dehydration reaction, and they are not above about 3 ° C and preferably not above - should cause 10 ⁰ C.

The post-processes mentioned above in connection with the hydroboration reaction can likewise be used to modify the group at the 11-position in compounds prepared by the dehydration reaction.
Useful compounds that can be easily made by the above method are:

13β-Ethyl-3-methoxy-II "-hydroxy- or -acetoxy-18,19-dinorpregna-1,3,5 (10), 17 (20) -tetraene,

(10), 17 (20) -tetraen-l 1-one,

D / i-Ethyl-S-methoxy-11β-hydroxy- or -acetoxy-18,19-dinorpregna-1,3,5 (10), 17 (20) -tetraene.

Birch reduction and hydrolysis of the product

Compounds that contain a reduced Α-ring can by the well-known Birch reduction with, if necessary, the following hydrolysis process. So can connections of the general formulas

R ¹ /

RO

where R is a substituted or unsubstituted aliphatic group, R ^{1 is} an n-alkyl group with 1 to 3 carbon atoms, W is a hydroxyl or protected hydroxyl group or an oxo or protected oxo group, and in the second formula the ring A is a 4 (5) - Or 5 {10) -double bond, can be obtained by using a compound of the general formula

RO

subjected to the Birch reduction, to form a compound of the first product formula, which, if desired, can be hydrolyzed to form a compound of the second product formula and then, if the groups Y, W and R ^{2 are} not desired groups, these are replaced by a suitable post-process is formed. Suitably the group R is an alkoxy group, for example a methoxy or ethoxy group.

The Birch reduction can be carried out using an alkali or alkaline earth metal in liquid ammonia or a Amine can be carried out in the presence of an alcohol. Examples of suitable metals are potassium, Lithium, calcium and preferably sodium. The alcohol suitably has up to 6 carbon atoms " and is preferably ethanol. It is preferred that the Birch reduction be performed on a compound which does not have an 11> - or 11 ^ -acetoxy group which gives rise to the occurrence of a side reaction. The subsequent hydrolysis is preferably carried out under strongly acidic conditions, preferably using a mineral acid, for example hydrochloric acid, to form a 4-en-3-one product accomplished. Methanolic hydrochloric acid is a particularly suitable reactant for the Hydrolysis. Alternatively, the hydrolysis can be carried out under weakly acidic conditions, ίο, for example, with oxalic acid to form the 5 (10) -En-3-one, which is then isomerized to the desired 4-en-3-one in the presence of an acid or base can be.

The products of the reduction or hydrolysis process can be subjected to conventional post-processes, as mentioned above. For example, the pregna-4,17 (20) -dien-3-one-ll ^ -ols with formation of the corresponding 3-alkylene-dioxy-pregna-4 (5), 5 (10) - or -5 «)) , 17 (20) -diens are ketalized, which can then be modified by oxidation in the 11-position to form the 11-keto compound, which then forms the corresponding pregna-4,17 (20) -dien-3-one- l 1/3-ols can be reduced and hydrolyzed; these compounds are Customized ^r s useful because many corticosteroid hormones have 1 ^ hydroxy groups. Optionally, the pregna-2,5 (10), 17 (2 ()) -triene-l 1 n-ols can be oxidized to the corresponding 11-ones, which then to the desired pregna-4,17 (20) -dienes -3-on-II / S-ols can be reduced and hydrolyzed. This latter oxidation is suitably carried out by the action of dicyclohexylcarbodiimide in dimethyl sulfoxide.

In addition to the levels given above, there are a number of other levels that would be familiar to the steroid skilled in the art are known, which are necessary in certain cases in the above and the subsequent reactions could be. These are summarized:

(a) Oxidation / Reduction. If the product is any Stage has a U.-v-hydroxy group and an 11-oxo compound is desired, can can be achieved by a suitable oxidation process. Suitable reactants for this process are chromic acid and the Oppenauer reagent. If desired, an 11-hydroxy group in to oxidize a compound which contains an aromatic Α ring are preferably essentially neutral oxidation conditions applied: an example of a suitable reactant isi Pyridine / chromium trioxide. If one, an 11/3 hydroxy group-containing product is desired, this was then achieved by reducing the above given 11-ons by a suitable hydride Carrying agents, for example a borohydride or lithium aluminum hydride, can be obtained. On diesi Way can the epimerization at the II position can be achieved, whereby an access to the cortisol rows is created.

(b) esterification. Any hydroxy group in the product at any stage can be esterified by conventional methods, for example by reaction with the appropriate acyl halide, acid anhydride, or ester of the acylating acid with a lower Al ⁶ scanol.

(c) Coalize. Any keto group in the product at any level can normally be passed through Reaction with the appropriate alkylcnglycol, wi

\ ethylene glycol in the presence of, for example, p-touolsulfonic acid, be ketalized.

(d) hydrolysis. Compounds of any ketal chain Hydroxy group-containing stage or of dben (b) and (c) can to form the corresponding Compounds containing free hydroxy and keto groups are hydrolyzed. Ester groups can be removed under acidic or basic conditions, while the ketal groups normally are removable under acidic conditions.

It is well known that in the synthesis of a compound containing a number of hydroxy or keto groups it is often necessary to protect certain hydroxy or keto groups while other hydroxy or keto groups in the molecule are to be modified, for example by reduction and / or oxidation.

Examples of suitable, protected oxo and hydroxy groups are in Djerassi, »Steroid Reactions - An Outline for Organic Chemists ", 1963, Chapter I, pp. 1 to 87, published by Holden-Day, to find. Protected oxo groups encompass ketals, thioketals, hemithioketals, thiazolidines, Schiffsche Bases, enol esters, enol thioesters, enol ethers, enol thio ethers, enamines, cyanohydrins, bismethylenedioxy groups. Semicarbazone, Oxime, and Girard reagents. A suitable protected oxo group is the ketal group. Suitable ketal groups are ethylenedioxy, propylenedioxy and 2,2-dimethylpropylenedioxy groups. Protected hydroxy groups include acylates, cathylates, ethers including cyclic, tetrahydropyranyl and trityl ether, cyclic carbonates, ortho esters, cyclic sulfites and nitrate esters.

Suitable protected hydroxy groups are acyloxy and alkoxy groups. It goes without saying every steroid chemist knows which of the above are recommended Groups for protecting a particular hydroxy or oxo group are suitable.

The reactions given above can be used in a multistep process for the preparation of useful compounds such as IS / I-ethyl-IS.IQ-dinorpregna-4,17 (20) -dien-3-one-II /? - oI, such as this from Fig. 1 can be seen. 13 / 9.17 / x-diethyl-3-methoxygona-1,3,5 (10), 9 (II) -tetraene (I) is formed with the formation of the corresponding Gona-1,3,5 (10) -IrICn -IlOi-OIs (II) hydroborated, which after acylation to the 1H-acyloxy compound (III) with the formation of IS / I-ethyl-1H-acyloxy-S-methoxy-IS ^ -dinorpregnal, 3,5 (10), 17 (20) -tetraene (IV) is dehydrated. This latter compound is hydrolysed to form the Ha-OI (V) according to Birch, ζ. B. in the presence of lithium in liquid ammonia and ethanol to the corresponding pregna-2,5 (10), 17 (20) -triene (VI), which is then reduced under strongly acidic conditions to form the 13/9 ethyl-l 8,19-dinorpregna-4,17 (20) -dien-3-one-ll \ -ols (VII) is hydrolyzed. The stereochemistry at the 11-position is reversed by 3-ketalization to form the pregna-4,17 (20) -dien-3-one, 3-ketal (VIII), oxidation to the corresponding H-one (IX), reduction with sodium borohydride and Dckctalisierung with formation of the key intermediate product 13 /? - ethyl-18,18-dinorpregna-4,17 (20) -dien-3-one-1 lß-ols (X). In an optional process route, the Pregna-2,5 (10), l7 (20) -triene-ΙΙίΛ-οΙ (VI) with chromium trioxide / pyridine or aluminum isopropoxide with the formation of 13 / f-ethyl-Ί - mclhoxv -18. V) - dinornreuna - 2Λ10). 17 (20) -Iricn-11-one (XIl) is oxidized, which is then reduced to the corresponding II /? - hydroxy compound (XIlI) and hydrolyzed to form the desired compound (X). The compounds (VII) u _n d (X) can easily be acylated, acetylated, for example, be the corresponding IH and 1 l / form - acyloxy compounds (XIV) and (XI). which are also useful as intermediates.
. It goes without saying that a steroid chemist should

ίο is able to do so without further ado. numerous options To consider ways which are obviously equivalent to the above sequence of reactions.

The compounds prepared according to the preceding process steps (a) to (e) are by the general formula (i)

(i)

explains in which R ^{1 is} an n-alkyl group having 1 to 3 carbon atoms, R ^{2 is} a hydroxyl or protected hydroxyl group and R ^{3 is} an ethyl group [st, or in which the radicals R ^s and R ³ together form an ethylidene group, W is an oxo or protected oxo or a <% - or ^ -hydroxy or protected hydroxyl group, Y is a hydroxyl or a protected hydroxyl group, in which case the ring A is aromatic, or a protected oxo group is in the simultaneous presence of a double bond in the 4 (5), 5 (6) or 5 (10) position, with or without a second double bond in the 2 (3) or 3 (4) position, or an oxo group, in which case the rings A uad B contain a double bond in the 4 (5), 5 (10) or 5 (6) positions.

Some of these compounds have pharmaceutical activity such as steroid hormone activity or anti microbiological effectiveness. Examples of suitable protected oxo and hydroxy groups are given above.

Particularly suitable, protected oxo groups for Y are ketals, preferably with the simultaneous presence a single double bond in the 5 (6) or 5 (10) positions, enol ethers preferably with simultaneous Presence of two double bonds in the 2 (3) and 5 (10) positions and enamines are preferred with the simultaneous presence of two double bonds in the 3 (4), and 5 (6) or 5 (10) positions.

Ketals are suitable for W groups. Examples of suitable ketal groups are ethylenedioxy, propylenedioxy and 2,2-dimethylpropylenedioxy groups. Protected hydroxyl groups include esters (acylates), generally cathylates, ethers, generally acetonides, cyclic carbonates, ortho-esters, cyclic sulfites, nitrate esters, tetrahydropyranyl and tetrahydrofuranyl ethers and trityl ethers. Particularly useful for the groups Y, W and R ² are lower carboxylic esters, e.g. B. acetate groups and ethers z. B.

Alkoxy groups. It is immediately clear to a person skilled in the art which of the above groups to protect a particular hydroxyl or oxo group are suitable.

Where the groups R ² . W and Y cine acyl or

Contain ester group, it is preferably an aliphatic or aromatic carboxylic acyl group having up to 20 carbon atoms; Examples of suitable acyl groups are acetyl, propionyl, phenylacetyl, / f-phenyl-propionyl and benzoyl groups. The acyl group can also be one derived from an organic sulfonic acid, for example a p-toluenesulfonyl group or a mesyl group. If the groups R ² , Wound Y are or contain an ether group, this is preferably a methoxy, ethoxy, tetrahydropyranyl-oxy, tetrahydrofuranyloxy, methoxymethoxy or dihydroxypropyloxy group. The term "alk-oxy," as used in this specification, alkoxide radicals which originate from an alcohol, in the absence of the hydrogen atom or its hydroxy group, and the term alcohol refers to organic compounds that generally contain hydroxyl groups.

The oxidation states

The oxidation in the 17, 20 and 21 positions is preferably carried out as a two-step process. For example, the 17 and 20 positions oxidized first and then the 21-position. Alternatively, the 17-position can be oxidized first and then the 20- and 21-positions. In general any suitable known oxidation method can be used. In detail reference is made to such methods as are described by F i e s e r and Fieser, Steroids, Reinhold, 1959, Chapter 19, are recorded.

The oxidation in the 17 and 20 positions is preferably carried out by oxidative hydroxylation or, carried out an epoxidation. The oxidative hydroxylation is preferred through the use an oxidizing agent in the presence of a catalytic amount of a suitable osmium compound, preferably achieved osmium tetroxide. Suitable oxidizing agents are tertiary amine or Pyridine N-oxide-hydrogen peroxide complex; Perchloric acid can also be used as an oxidizing agent. The tertiary amine is preferred an N-alkylmorpholine or a trialkylamine, for example Triethylamine.

The oxidative hydroxylation, when carried out on an 18,19-dinorpregn-17 (20) -ene, normally introduces a * -hydroxy group in the 17-position and an oxo group in the 20-position, although a certain amount of corresponding Πχ , 20β- diol is formed as a secondary product. The amount of n ^ O / I diol formed can be kept to a minimum if the reaction is carried out at a relatively high temperature, about 40 ^° C., over a short period of time (about 3 hours). If the reaction is carried out at room temperature for about 2 days, the 17%, 20/3 diol amount increases.

To explain the oxidative hydroxylation, IIA-acetoxy-n / f-ethyl ^ -methoxy-lS.lQ-dinorpregna-l, 3,5 (10), 17 (20) -tetraene, osmium tetroxide, pyridine and tertiary butanol are used at room temperature during treated over a period of 2 days with a 6-fold excess of Triäthylaminoxitl hydrogen peroxide complex. The resulting mixture is purified by conventional extraction, chromatographic and crystallization techniques to produce 11 -v-acetoxy-IS / S-ethyl-S-methoxy-IS, ^ - dinorpregna-1,3,5 (10) -triene-1,7 \-ol-20-one worked up The epoxidation is usually by means of a peracid ^Ex: elsweise m-chloroperbenzoic acid, achieved Monopernhthalsäure, performic acid, peracetic acid or Perfiuoressigsäure. Acid hydrogen peroxide can also be used. Suitable solvents for the epoxidation reaction are inert solvents, for example ethers and halogenated hydrocarbons such as chloroform. In order to avoid side reactions, it is preferred to carry out the reaction at a relatively low temperature; O ⁰ C is a suitable temperature. If the epoxidation is carried out on a Pregn-17 (20) -ene, the product is largely the 17th \, 20th-v-epoxy derivative; when using monoperphthalic acid, a high yield of this latter compound can be achieved in the above reaction.

The 17 ^, 20 «-Epoxyverbindungen can be in the corresponding 17 "-ol-20-ones can be converted in various ways. For example, the epoxy ring under strongly acidic aqueous conditions with acid, for example with perchloric acid, to the corresponding 17 \, 20/9 diol are split, which then oxidized to the desired 17x-ol-20-one can. Alternatively, the epoxy group can be oxidized directly to the 17λ-Ο1-20-οπ. Explanatory Compounds made by oxidations at the 17 and 20 positions have the general Formula (ii)

(ü)

where R ^{1 is} an n-alkyl group having 1 to 3 carbon atoms, R ^{2 is} a hydroxy or protected hydroxy group, W and X <x or / 9-hydroxy or protected hydroxy groups, or oxo or protected oxo groups, or X and R ² together form an epoxy group, Y is a hydroxyl or protected hydroxyl group, in which case ring A is aromatic, or a protected oxo group, in which case rings A and B have a double bond in the 4 (5) - , 5 (10) - and 5 (6) positions with or without an additional double bond in the 2 (3) or 3 (4) position, or an oxo group, in which case rings A and B are a Have double bonds in the 4 (5), 5 (10) or 5 (6) positions. These compounds have corticosteroids and / or other hormonal activities or are intermediates in the preparation of such compounds. Some of these compounds show antimicrobial or antiprogestational activity.

Examples of suitable protected oxo and hydroxy groups are given above.

To explain the oxidation at the 17 and 20 positions, compounds of the general formula (ii) in which R ¹ , R ² , X, Y, W and the unsaturation in rings A and B have the meaning given above, dur; h oxidation can be produced, e.g. B. by means of an oxidative hydroxylation or

Epoxidation of a compound of the general formula

where R ¹ and W have the same meaning as above and Y is a hydroxyl or protected hydroxyl group, in which case the ring A is aromatic, or an oxo group, in which case the rings A and legs have a double bond in the - or5 (10) division, or a protected oxo group, in which case rings A and B have a double bond in the 4 (5), 5 (10) position, with or without a second double bond in the 2 (3) - or 3 (4) position and then subsequently, if the groups R ² , X, Y and W and the unsaturation in the rings A and B are not as they are desired ij, these subsequently by at least a suitable post-process can be established. Examples of compounds that can be produced by the above oxidative hydroxylation are:

30th

35

II, *, 17 * -diol, ethylene ketal;

13 / S-ethyl-llft- or -ll
pregn-4-en-3,20-dione-l 7 * -ol;

IS / J-ethyl-11a-acetoxyO-methoxy-ISJQ-dinorpregna-1,3,5 (10) -trien-20-one-17 \ -ol;

40

pregna-l, 3,5 (10) -trien-17 "t-20i? -diol.

Suitable starting materials for oxidative hydroxylation or epoxidation are the following:

13 / S-ethyl-lla- or -llß-hydroxy-18,19-pregna-4,17 (20) -dien-3-one, ethylene ketal;

13 / J-Ethyl-IIIa- or -II / J-acetoxy-ISJ
pregna-4,17 (20) -dien-3-one;

lS3-ethyl-lloi-acetoxy-or-hydroxy-S-methoxy-18,19-dinorpregna-1,3,5 (10), 17 (20) -tetraene.

50

The products of the oxidative hydroxylation, which, as mentioned above, are compounds of the general formula (ii) in which R ^{a is} a hydroxyl group and X is a hydroxyl or oxo group, can be used in various conventional post processes, e.g. B. as stated above, are subjected. For example, any oxo group present in the molecule can be converted to the corresponding ketal. This type of post-process is of particular importance because in this way an oxo group can be protected while another part of the molecule is modified, for example by reduction. It should be pointed out that ketalization is not the only process for protecting oxo groups which can be used in the present case; many, if not all, of the techniques mentioned in this specification can be used. The protected oxo groups can be converted back to their starting oxo groups by, for example, acid hydrolysis.

The oxylated functions present in the molecule can also be modified (or protected) by conventional reactions such as hydrolysis, esterification, reduction and oxidation. For example, the Wx or 11/3 hydroxy compounds can be converted to the corresponding acyloxy compounds; the acyloxy groups can, if desired, be subsequently removed by hydrolysis or reduction. Furthermore, the 11λ- or 11/3-hydroxy compounds can be converted into the corresponding 11-ones, for example by reaction with chromic acid or under the conditions of the Oppenauer reaction, preferably using essentially neutral oxidation conditions, such as pyridine and chromium trioxide, if ring A is aromatic. These 11-ones can easily be converted back to the 11-hydroxy compounds, if lithium aluminum hydride or a borohydride is used in the reduction the product is largely a 11 / J-hydroxy compound, although some 11-hydroxy compound is formed. It can be seen from this that this oxidation / reduction sequence enables Ila-hydroxy compounds to be converted into 11/5 hydroxy compounds, in order to open the way into the cortisol series of hormones. Alternatively, if the product of the oxidative hydroxylation is a 17 \, 20 / J-diol, this can be converted to the corresponding 17 / x-ol-20-one by oxidation; a suitable reactant for the oxidation is dimethyl sulfoxide in acetic anhydride.

The compounds containing an aromatic ring A can be obtained by using the Birch reduction modified with subsequent hydrolysis under suitable conditions. For example, can a Ha- or II / S-Hydroxy-S-methoxy-ISJQ-dinorpregna-1,3,5 (10) -trien-20-one-17 (X-olnach Protecting the 20-one group by, for example, ketalization, by the action of an alkali metal or alkaline earth metal (for example lithium, sodium, potassium or calcium) in liquid ammonia in the corresponding Hoc- or II / 9-hydroxy-3-methoxypregna-2,5 (10) -dien-20-one-17ot-ol, ketal are converted, which under weak or strongly acidic conditions with formation of the 5 (10) - or 4-en-3-one, namely the H * - or II / J-hydroxy-lS.lQ-dinorpregn-5 (10) - or 4-en-3,20-dione-17 ^ -ol can be hydrolyzed. If desired, the protection of the 3-on group, made possible by the enol ether moiety mentioned above, during the conversion a 11 * - to ll /? - hydroxyl group applied will. Thus, a 11 \ -hydroxy-3-methoxy-18,19-dinorpregna-2,5 (10) -dien-20-one-l7rx-ol, ketal be converted by oxidation into the H-On, which, as mentioned above, to the corresponding 11ß-hydroxy 3-methoxy-18,19-dinorpregnadiene are reduced to the 4- or 5 (10) -En-3-one, as already stated represents, can be hydrolyzed.

It is preferred to perform the Birch reduction on a compound other than / J-acetoxy group in the 1! position has to prevent the occurrence of voi Prevent side reactions.

Most, if not all, of the post-processes listed above may apply to Epox products dation reaction can be applied, which like bereii

22nd

^ ^, a ^ toxy - ^ - losyloxy-lS.l ^ dinorpregn ^ -nn-B-on-

delusions, usually l ^, 20 * -epoxy compounds - ^ _umg , _{se (zt we} j _{en Dic E} poxidür, -un _gi .

are if the excavated material ^ e 17 (20) -Dopp.i ^ ^ ^ _η . _ο applied to connections

binding contains. In addition, the } ^Ί % ™ ^ ° **. _be ; n that unleash an aromatic A-Rm ₃

d thnd 17 "OI-20-one um- k 13 / iAthll 1 ^ acetoxyVmeth

binding contains. Additionally }% ^. _will ; n, the one

connection to the corresponding 17 «-OI-20-on um- _pHsw . _iss can 13 / i-Athyl-l 1 ^ acetoxy.methoxy-

to be converted. For example, 4 «epoxy - ^. ^ _Η 3_ _{1ι3> 5 (} ΐ0), 17 (20ΗίΙ _Γ αΜ (L) / u dir

group under-strongly acidic water: n ^B f ^^ enisprwhenden 17 *, 20 * -Epoxyverbindunu (7th) ep ,,

forming the corresponding 17 *, 2U / J-u! oi!> g, which are then treated as above

are columns, which then to the ge ^Wun f ^ht f "™ _n

17 * -Ol-20-one can be oxidized, or alternatively ^ - ^ ^ ^ _S teroid = hemiker clear, that the above

, the epoxy group to the ux-vi _V out follow bsi compound by stirring immediately advertising

20-one can be oxidized. _Pr purifies the ability, in weaving R ¹ no ethyl groups, but

The in F i g. 2 shown reaction _{sequence explains α ^ a Methyi} . _or n-propyl group j _sl .

Possibilities of oxidative hydroxylation or ErJ, ^ _means no for the sleroid chemistry

Epoxidation, and it can be passed on, as e _chwier j » _ke it numerous other variations of the above

mentioned above, to find 15 * ™ * J ^S ' _reaction sequences for the production of useful compounds. d: e jeJach

fertilizing can be used. 13 /? - Athy1-18 IM.no- ^^ _jva , _{enle of the} actually operated

di3l ethyl ketal (A) we - clear aq

Qungen verwciiuci »v.iu \, u. * - _r ., -

pregna-4,17 (20) -dien-3-one-lH-ol, ethylene ketal (A), wel- clear equivalents aer i = n ches in Fig. 1 which is compound XIV, will have been shown to drive oxidatively_ to 18,19-Dinorpregn-4-en-3,20-dione-lU, 17 ^ -diol, The 17x, 20j? -Diol (X) se.vifft one above

3-Ethylene ketal (B) hydroxylated, which then under 20 further route to the synthesis of the cortical tendons. Formation of ^ -ethyl-lS ^ -dinorpregn ^ -en- ^ ll ^ O- This can form the 20 /? - To> yl compound trion-17 * -ol, 3-äthylenenketal (C) oxidiertwird.l3 / S-Äthyl- take place, which then according to conventional methods lla-acetoxy-18,19-dinorpregna-4,17 (20) -dien-3-one (D) becomes the corresponding 20-Εη-Π * -ol or 17 (2O) -En oxidatively hydroxylated to 13/3-ethyl-l 1-χ-acetoxy-21-ol can be converted, one of the same as lejg-dinorpregn ^ -en ^^ O-dione-nTc-oi (E), the 25 described above, being oxidative to the desired Oxo groups of this compound can be hydrolyzed to form the ent-17-v, 21-diol-20-one. on speaking diethylene ketal (F), this can cause oxidation in the 20 and 2! can then be effected with the formation of the free 1H, 17 \ -diles.

ols (G) is subjected to hydrolysis, after which oxi- The oxidation at the 21-position is preferred

dation to the ll-On-17 \ -ol (H), reduction to 30 carried out by acyloxylation. I1 / 9.17 * -Diol (J) and decetalization 13 / J-Ethyl- The acyloxylation is preferably after a

18,19-dinorpregn-4-en-3,20-dione-II / i, 17T <-diol (K.) he carried out two-stage process in which there are. An optional route involves the oxidative Hy-21-halo compound, preferably the 21-bromodroxylation of Dβ-ethyl-1H-acetoxy-S-methoxy or iodine compound, is formed first and this 18,19-dinorpregna-1,3,5 (10), (20) -tetraen (L), which in 35 connection then in the corresponding 21-Acyioxy-Fig. 1 is the compound IV is converted to form the compound. Preferably the 17-ol-20-one is (M), the 20-one group of this acyloxy group being an acetoxy group. Compounds, compound by ketalization with the formation of a 21-iodine group, can be protected by Um-ketal (N), and then after setting the corresponding 17/3 acetyl compound with removal of the acetyl group to form the 20-on 40 preferably Iodine under mild, basic conditions lloi.n'x-diols.n-Äthylenketals (O), implementation of the produced, for example calcium oxide and Birch reduction and hydrolysis under acidic conditions calcium hydroxide in the presence of an organic gungen, whereby 13.3- Ethyl-18,19-dinorpregn-4-en-peroxide, for example cumene hydroperoxide or perll-x, 17-diol-3,20-dione (U) is obtained. Optionally, oxidic tetrahydrofuran with formation of the 2l-iodine can form the Birch compound to the pregna compound. Preferably, should the temperature of 2,5 (10) -diene (P) can be reduced, which can then not up to the reaction over 30 ⁰ C increase. The successive 11-On (Q) oxidized to the II /? - Ol (R) 21-bromine compound can be reduced by reacting the can be reduced with simultaneous hydrolysis of the speaking 17/3-acetyl compound with a quarter enol ether and the ketal groups to form the nerar Ammonium bromide perbromide, for example, desired compound (K). In this latter 5 ° of the pyridine compound can be produced. The 21-iodo-oxidative hydroxylation is n / I-ethyl-lK-acet or -bromo compound can be linked to the corresponding oxy-3-methoxy-18,19-dinorpregna-1,3,5 (10) -triene-21-acetoxy compound by reaction under Rück-17oc, 20 /? - diol (La) also formed; This compound fluxes in 1 to 18 hours with an alkali metal acetate, can, as described above, to the compound (M), for example sodium acetate, be oxidized in the presence of a, whereby the yield of the last 55 suitable solvent, for example acetone and the compound mentioned from the oxidative hydroxyl may be increased with the addition of acetic acid and / or lation. Dimethylformamide, are implemented.

To explain the epoxidation reaction and, if desired, one needs the 21-bromine or

its post-process is not to isolate OSS-ethyl-lK-acetoxy -Jodverbindung but can these 18,19-dinorprcgna-4,17 (20) -diene-3-one (D) corresponds to ^6o directly in the 21- Acyloxy compound converting speaking 17 \, 20 \ -epoxy compound (V) epoxidized, A preferred, alternative method of 21 -oxi-

which then consists of a halogenation or reaction of 18,19-diiiorpregna-4-en-20-one-17 \ -oI (W) is oxidized with blood tetraacelate on a compound with the formation of 13β-ethyl-ll \ -acetoxydation Alternatively, the epoxy group of the compound (V) can lead, which contains the 4-en-3-one system, which has been protected in the form with the formation of the corresponding 17 \, 20 /? -diol (X) ⁶ 5 of a linamine salt, This process is suitably under acidic

dicrl wcrdiMi can. The compound (X) can also or approximately neutral conditions carried out with n-I oluolsullonsäiiie with formation of 13 / f-ethyl- The v / Z-bottom ketone can by the Reaklioi

protected with a primary or secondary amine to form the desired enamine, which is converted to a salt, preferably with a strong acid (salts with acids medium strength, provided that it does not hydrolyze excessively under reaction conditions will). It is preferred to use a secondary amine in which the nitrogen atom Part of a 5-membered ring is, as in pyrrolidine and in substituted pyrrolidines ^ as these enatnines particularly easy to form.

The acyloxylation can be carried out on a compound with a 20-oxo group or protected 20-oxo group, z. B. a ketal. This is preferably done by reaction with a halogen and then with an acylate anion, but this can also be done directly with a lead tetraacylate. Instead of a halogen, i. H. Chlorine, bromine, iodine, bromine iodide or bromine chloride, amine trihalides can be used or complex perhalides, such as phenyltrimethylammonium bromide perbromide, phosphorus trihalides, such as B. phosphorus tribromide, cyanogen bromide, halimides such as N-halosuccinimides, N-haloacetamides, sulfuryl halides, thionyl halides, tert-butoxyhalides with an oxidizing agent, e.g. B. a perchlorate, and copper halides, be used.

The above process results in 21 oxidation if not carried out after a Birch reduction is, or where such a reduction is not followed by hydrolysis, to be illustrative compounds of the general formula (iii)

- X

(iii)

wherein R ^{1 is} an n-alkyl group with 1 to 3 carbon atoms, X is a / 3 - [(2'-halogen, hydroxy or protected hydroxy -) -! '- (oxo or protected oxo) ethyl] - <\ - (hydroxy or protected hydroxy) -methylene group, W a * - or ^ -Hydroxy or protected hydroxy group or an oxo or protected oxo group, Y represents a hydroxy or protected hydroxy group and the ring A is aromatic or the 2,5 ( 10) -Dien-Sybtem contains. Such compounds have corticosteroids or other steroid hormone activity, e.g. B. estrogenic or corticosteroid effectiveness or are intermediate products for the production of such steroids.

Examples of suitable protected oxo and hydroxy groups are given above. Examples of such compounds are:

n / S-Ethyl-S-methoxy-il .- ^ l-diacetoxy-

18,19-dinorpregna-1,3,5 (10) -trien-1,7 * -ol-20-one

/ y I, 3,5 (10) -trien-20-one-II *, 17 ", 2l-triol.

When the group X contains a halogen atom it is preferably iodine, although it can be chlorine or bromine

To illustrate, compounds of the general formula (iii) in which R ^{1 is} an n-alkyl group having 1 to 3 carbon atoms, X is a - [(2'-hydroxy- or protected hydroxy-) - l'-hydroxy-, protected hydroxy -. Oxo or protected oxo) - ethyl] - «- (hydroxy or protected hydroxy) - methylene group, W is a <x- or / J-hydroxy or protected hydroxy group or an oxo or protected oxo group, Y is a hydroxy or protected hydroxy group is ίο and the ring A is aromatic or contains the 2,5 (10) -diene system, by oxidizing a compound of the general formula

are prepared, in which the groups R ¹ , W and Y and the unsaturation in ring A have the meaning given immediately above, Z is an oxo group and R ^{2 is} a hydroxyl group or protected hydroxyl group and then, if the groups W, Y, X , R * and the unsaturation in ring A are not the desired, can be converted into the desired compounds by one or more subsequent processes.

Examples of compounds which are produced by the acetoxylation reaction given above, are:

13/9-ethyl-11a- or - / S ^ l-diacetoxy-O-methoxy-18,19-dinorpregna-1,3,5 (10) -trien-17 «-ol-20-one

13/9-Ethyl-21-acetoxy-3-methoxy-18,19-dinorpregna-1,3,5 (10) -trien-17tt-ol-ll, 20-dione.

Suitable starting materials for the acyloxylation reaction are:

130-ethyl-IIIa- or - / 9-acetoxy or -hydroxy-3-methoxy-18,19-dinorpregna-1,3,5 (10) -triene-
17 "-ol-20-one

13 /? - Ethyl-3-melhoxy-18,19-d inorpregnal, 3,5 (10) -trien-17a-ol-ll, 20-dione.

The products of the acyloxylation reaction in which X is a /? - (2'-acyloxy-r-oxo-ethyl) -m- (hydroxy or protected hydroxy) -methylene group and the ring A is aromatic or the 2,5 (10) -diene containing system, various conventional post-process may be subjected. For example, any acyloxy group present can be converted to the corresponding hydroxy compound by reduction or by hydrolysis. A 21-acetoxy-20-oxo-17'-hydroxy compound can lead to the corresponding

20-oxo-17 «, 21-dihydroxy compound converted will. Compounds of this latter type can be protected on the 20-oxo group by ketalization so that other procedures can subsequently be carried out. In this way the Corti

^The secondary chain is protected in such a way that other post-processes, such as reduction, both according to Birch "and with borohydride, can be carried out without damaging the secondary chain.

/ if

Other post-processes that can be done are those in which any are present 3-oxo group is ketalized and any hydroxyl groups present are acylated or etherified. The decetalization can be effected under acidic conditions.

It is preferable to perform the Birch reduction on a compound that is in the 11-position has no /? - acetoxy group in order to avoid the occurrence of side reactions.

The reaction sequence shown in Fig. 3 explains the possibilities according to which the acetoxylation and the above-mentioned post-processes are carried out to prepare useful compounds be able. n / I-Ethyl-11ft-aceloxy-S-methoxy-ISJQ-dinorpregna-1,3,5 (10) -trien-20-one-17a-ol (A) (compound M in Fig. 2) is via the 21 -iodine compound (B) to the corresponding lla, 21-diacetoxy compound (C) acetoxylated, which then leads to 13) 3-ethyl-3-methoxypregnal, 3,5 (10) -trien-20-one-llrt, 17a, 21-triol (D) is hydrolyzed. The 20-oxo group of this compound is under Protected formation of the Äthylenenketal (E), which is then subjected to the Birch reduction to form the Pregna-2,5 (10) -diene (F) with subsequent acetylation at the 21-position and oxidation to the 11-on (G) and reduction and hydrolysis to form the 18-homo-19-norcortisol (I) via the 20-K.etal (H) as Interconnection.

It is clear to the steroid chemist that the above reaction can also be carried out with compounds in which R ^{1 is} not an ethyl group, but a methyl or n-propyl group. In addition, it is not difficult for the steroid chemist to make many other modifications to the reaction scheme given above that would be the obvious equivalents of that described herein.

The methods of 21-Oxidaiion given above after carrying out the Birch reduction and hydrolysis stages lead in an illustrative manner to compounds of the general formula (iv)

Examples of suitable protected oxo and hydroxy groups are given above.

If X contains protected oxo groups, or W and Y are such, they are preferably ketal groups. Suitable ketal groups are ethylenedioxy, propylcndioxy and 2,2-dimethylpropylenedioxy groups.

Protected hydroxyl groups include acylates, cathylates, ethers including cyclic ethers, Tetrahydropyranyl and trityl ethers, acetonides, cyclic carbonates, ortho-esters, cyclic sulfites and nitrate esters. When X contains protected hydroxy groups, or Y and W are such groups, they are preferred Acylates and alkoxy groups. It will be clear to a steroid chemist which of the above are given Groups for protecting a particular hydroxy or oxo group are suitable.

When the group X contains a halogen atom, it is preferably iodine, although it is also chlorine or bromine can be.

For illustration, compounds of the general formula (iv), in which R ^{1 is} an n-alkyl group with 1 to 3 carbon atoms, X a /? - [2 '- (hydroxy- or protected hydroxy) -l' - (hydroxy or protected hydroxy, oxo- or protected oxo) -ethyl] -A- (hydroxy

or protected hydroxy) methylene group, W a λ- or / Ϊ-hydroxy or protected hydroxy group or an oxo or protected oxo group, and Y is an oxo, hydroxy or protected hydroxy group, in which case the rings A and B have a double

binding contained in the 4 (5) or 5 (10) position, or a protected oxo group, where ~ the rings A and B have a double bond in the 4 (5) -, 5 (10) - or 5 (6) position, with or without a second double bond in the 2 (3) or 3 (4) position, durcli

Oxidation of a compound of general form

R ¹

(iv)

wherein R ^{1 is} an n-alkyl group with 1 to 3 carbon atoms, X is a /? - [2'-halogen (hydroxy or protected hydroxy) -l '- (oxo or protected oxo) ethyl] - «- (hydroxy or protected hydroxy) methylene group, W is a tx- or / f-hydroxy or protected hydroxy group or an oxo or protected oxo group, and Y is an oxo group if rings A and B have a double bond in the 4 (5) or 5 (10) -position, or a protected oxo group, if the rings A and B have a double bond in the 4 (5) -, 5 (10) - or 5 (6) -position, with or without a second double bond in the 2 (3) or 3 (4) position included. Such compounds have corticosteroids and / or other hormonal activities or are intermediates in the preparation of such compounds.

are prepared, in which the groups R ¹ , W, Y and the unsaturation in the ring A have the meaning given above, Z is an oxo group and R 'is a hydroxyl or protected hydroxyl group and then, if the groups W, Y, R ² X and the unsaturation in rings A and E are not as desired, these are subsequently formed by one or more post processes.

Examples of compounds which can be produced by the reaction given above are

l ³ ^ -Ethyl-21-acetoxy-18,19-dinorprcgn-4-en-3,20-dione-ll «- or -β, Ώ & -ά \ ο \.

13/3 ethyl II ". or -110,21-diacetoxy-18,19-dinorpregn-4-en-3,20-dione-17 * -ol.

/ yWlacetoxylS ^ -dinorp
j, ll, 20-tnon-17a-ol, 3-ethylene ketal.

27 28

Suitable starting materials for the reaction compound (P) can be hydrolyzed. Secondly

are: can similar reaction processes be carried out on the ll /? -acet-

"V, _ni , _1ιΛ iRiOH'nnr oxyderivat (U) of the compound (R) via the intermediate

! ./ i-Atnyi-ii / x-oaer-ii / J-aceioxy-iö ^ y-amcr- products (V) and (W) to form the compound (P)

^{H e} 5 to be carried out. Finally, 13 /? - Athyl-

Ll / S-Äthyl-ie. ^ - dinorpregn ^ -en-S ^ O-dione-lla- 21-acetoxy-20,20-ethylenedioxy-3-methoxy-18,19-dinor-

or - /? - diol and pregna-2,5 (10) -dien-ll /? - oI directly for connection

IS / J-Ethyl-lS ^ -dim ^ regn ^ -en-SJl ^ O-trion- ^clun 8 ( ^p ) are hydrolyzed.

17 / x-ol-ethylene ketal. Further examples that are

Lo possibilities of the invention for making more useful

The products of the general formula (iv), in which X corticosteroid compounds can be used-

a /? - (2'-Acy! oxy-l'-oxo) -äthyl-a- (hydroxy or genes, are given in Figs. 5 and 7,

protected hydroxy) methylene group, 13/3 ethyl

subjected to various conventional post-processes - 3 - methoxy - 11λ - acetoxy - 18.19 - dinorpregna-

will be. For example, any 15 l, 3.5 (10), 17 (20) -tetraene (IV) present can be oxidatively formed to form

Hydroxy group to the corresponding acyloxy connection of the corresponding Pregna-l, 3,5 (10) -triene-17 * -ol-

formation can be esterified, while any 20-ones (XV) present are hydroxylated, that after formation

Acyloxy group to the corresponding hydroxy compound of 20-ethylene ketal (XVI), under basic conditions

by reduction or hydrolysis to 13 /? - EthyI-3-methoxy-20,20-ethylene-di-

can be converted. A 21-acetoxy-20-oxo-17 "-hy-20 oxy-18,19-dinorpregna-1,3,5 (10) -triene-II", 17ot-diol

In this way, the hydroxy compound can be hydrolyzed to the corresponding (XVIl). This ketal is then

corresponding 20-oxo-17a, 21-dihydroxy compound by means of Birch reduction to the corresponding pregna-

to be changed. 2.5 (10) -diene (XVIII) reduced, which is then under

The reaction processes in FIG. 4 explain the formation of the important intermediate product 13 /? - ethyl

Possibilities of using the compounds of the general 25 18,19-dinoφΓegn-4-en-ll. <X, 17 '* - diol-3,20-dione (XIX)

To produce formula (iv). 13 ^ -Ethyl-ll-v-acetoxy- can be hydrolyzed.

18,19-dinorpregn-4-en-3,20-dione-17a-ol (A) (Compound- The above mentioned dione (XIX) is then used for

dung W in FIG. 2) is via the 21-iodine compound (B) corresponding 21-acetoxy compound (XX) acetoxy-

with the formation of Dß-ethyl-llrv ^ l-diacetoxylated, which then leads to the corresponding 21-acetoxy-pregn-

18,19-dir.orpregn-4-en-3,20-dione-17 "-ol (C) acetoxy-3 ° 4-en-17-v-ol-3, ll, 17-trione (XXI) oxidized can be,

lates. which after hydrolysis to 11λ, 17λ, 21-Τπο1 (Ε>) This last-mentioned compound can with formation

treated with ethylene glycol and p-toluenesulfonic acid from 13ß-EthyI-18,19-dim ^ regn-4-en-17 (Tc, 21-diol-3, ll,

and then with formation of the intermediate 20-trione (18-homo-19-norcortisone) (XXII), which

Dukts 13 /? - Ethyl-21 -acetoxy-20,20-ethylenedioxy- bare hormonal activity has to be hydrolyzed.

18,19-dinorpregn-4-en-3-one-ll \, 17-diol (E) acetylated 35 In addition to the above process route

will. for 18-homo-19-norcortisone there is also a large one

The key intermediate product given above is the number of other possible synthesis pathways. Examples

can be in the 13 /? - ethyl-18,19-dinor- in two ways:
pregn-4-en-3, ll, 20-trione-17rt-ol (F) (18-homo-19-nor-

cortisone). Compound (E) 40 (1) 13/3-ethyl-18,19-dim ^ regna-4,17 (20) -diene Ketalized to the corresponding 3-ketal (H), IIIi-ol-3-one, etnylenketaI (VIII) (see Fig. 1) becomes oxiwelches is oxidized to the 1 l-oxo-3-ketal (J), which is datively hydroxylated and slightly with the formation of the intermediate hydrolyzed with acid to give the corresponding compound (F) product (XIX), which is then hydrolyzed to 18-homohydrolyzed can be. Optionally, the compound 19-norcortisone is converted as described above (E) can be converted directly to 13 /? - ethyl-21-acetoxy- 45.

20,20-ethylenedioxy-18,19-dinorpregn-4-en-3, ll-dione (2) 13/3-ethyl ll <»acetoxy-3-methoxy-18,19-dinor-

(K) oxidized, which leads to compound (F), as indicated above, 3-5 (10) -trien-i7 <»ol-20-one (XV) (see Fig. 5)

give, can be hydrolyzed. becomes the corresponding 11, 21-diacetoxy compound

In another process route is 13 /? - Ethyl- (XXlIl), being the 20-On group of this compound

18,19-dinorpregn-4-en-ll, 20-dione-17 /) (- oI, 3-ke-50 is protected by ketalization, with the formation of the

tal (L) (compound C in Fig. 2) via the 21-iodine-corresponding 20,20-ethylenedioxy-II «, 21-diacetoxy-

bond (M) to the 130-ethyl-21-acetoxy-18,19-dinor compound (XXIV) acetoxylated. which then under basic

pregn-4-en-3, ll, 20-trion-17a-ol, 3-ketal (N) acetoxy- see conditions for 13 /? - ethyl - 3 - methoxy-

liert, which hydrolyzes to the desired compound (F) 20.20 - äthylendioxy - 18.19 - dinoφregna - 1,3,5 (10) -

can be. 55 trien-ll «, 17r *, 21-triol (XXV) is hydrolyzed. This

The above-mentioned compound (J) can also be the latter compound is then the Birch-Reduk-

ym production of 13 /? - ethyl-18,19-dinoφregn-4-en- tion and subjected to the corresponding Pregn-4-en-

3,20-dione-II / ?, 17a, 21-triol (P) (18-homo-19-norcortisol 11 *, 17λ, 21 triol-3,20-dione (XXVI) hydrolyzes, the

or 18-homo-19-norhydrocortisone) can easily be used to produce the desired 18-homo-19-norcortisone

if you can oxidize this reduction with a boron 60 (XXH). The intermediate product

hydride to form the Π / Ϊ-oil (Q), (XXVI) can also be obtained by hydrolysis of 13 /? - ethyl

which after hydrolysis the desired compound (P) 21 - acetoxy -18.19 - dim ^ regn - 4 - en - 11λ;, 17α - di-

results. ol-3,20-dione (XX).

Other ways to compound (P) are: 13 /? - Ethyl- (3) 130 - Ethyl - 11 «- acetoxy -18.19 - dinoφregna-

18,19-dino ^ regn-4-en-3,20-dione-II / ?, 17Ä-diol (R) (Ver 65 4,17 (20) -dien-3-one (XIV) (s. Fig. 5) is under BiI-

bond K in Fig. 2), is via the 21-iodine compound of the corresponding pregn-4-en-17 «-ol-3,20-dione

dung (S) to 130-ethyl-21-acetoxy-18,19-dinoφregn- (XXVII) oxidatively hydrolyzed, which to 13 /> - ethyl-4-en-3,20-dione-II / ?, 17 «- diol (T) acetoxylated, which leads to 18.19 ^ ίηύφΓε§η-4-εη-1ΐΛ, 17Λ ^ ίοΙ-3.20 ^ ιοη (XIX)

is hydrolyzed, which in turn is converted into 18-homo-19-norcortisone (XXIl), as described above, can be converted.

(4) The compound (XIV) can in the presence of perphthalic acid with formation of 13 / i-ethyl-II \ -acetoxy- 17 *, 20 / x-epoxy-18,19-dinorpregn-4-en-3-one (XXVl 11) are epoxidized, which are oxidized to the corresponding Pregn-17A-ol-3,20-dione (XXVIl) can. This latter connection can lead to 13 /? - ethyl-18,19 - dinorpregn - 4 - en -11λ, 17λ - diol - 3.20 - dione (XIX) are hydrolyzed, which is converted into 18-homo-19-norcortisone (XXlI) as described above can be converted.

(5) The 17a, 20 * -epoxy compound (XXVIU) (s. F i g. 5), can be hydrolyzed in the presence of perchloric acid to the corresponding Pregn-17%, 20/3-diol-3-one (XXlX) that with dimethyl sulfoxide and acetic anhydride to 13 ^ -ethyl-llx-acetoxy-18,19-dinorpregn-4-en-17 "-ol-3,20-dione (XXVII) can be oxidized, which to 18-homo-19-norcortisone, such as described above, can be converted.

(6) The 17ct, 20 /? - diol (XXlX) (Fig. 5) obtained can be mixed with p-toluenesulfonyl chloride to form 13? - ethyl - IH - acetoxy - 20 /? - tosyloxy -18.19 - dinorpregn-4-en-17ix-ol-3-one (XXX) are reacted, which is then reacted with sodium acetate to form the corresponding pregna - 4.20 - diene -17- * - oil - 3 - ons (XXXl) is heated, which is then oxidatively hydroxylated to 13/9 - ethyl - Π * - acetoxy -18.19 - dinorpregn - 4 - en-17 «, 21-diol-3,20-dione (XXXIl). This latter compound can then be hydrolyzed to the corresponding pregn-4-en-1H, 17x, 21-triol-3,20-dione (XXXIII), which can be oxidized to 18-homo-19-norcortisone (XXII).

The process according to the invention can also be used for the preparation of the pharmacologically useful compound 18-homo-19-norcortisol (IS-homo - ^ - norhydrocortisone) (XXXVI), as in F i g. 6 is shown. An example of such a manufacture is the following:

13/9 - Ethyl - Ut - acetoxy - 18.19 - dinorpregna-4,17 (20) -dien-3-one (XI) is formed with the formation of the corresponding Pregn-4-en-17-x-ol-3, 20-dione (XXXIV) is oxidatively hydroxylated, which can then be acetoxylated to the corresponding II / i, 21-diacetoxy compound (XXXV), which can easily be converted to the corresponding 13/3 - ethyl - 18,19 - dinorpregn - 4 - en - II / U7 -x., 21-triol-3,20-dione (IS-homo-ig-norcortisol) (XXXVl) can be hydrolyzed. Alternatively, this latter compound can be obtained by a similar process sequence from 130 - ethyl -18.19 - dinorpregna - 4.17 (20) - dien-11 /? - Oil - 3 - one via Pregna - 4 - en - ΙΙβ, Πχ - diol-3,20-dione (XXXVlH) and the 21-acetoxy compound (XXXIX). The above-mentioned diacetoxy compound (XXXV) can, if desired, further to form 13 /? - Ethy! -110,17 *, 21-triacetoxy-18,19-dinorpregn-4-en-3,20-dione (XXXVl I ) are acetylated.

Referring to FIG. 7 becomes the Hx-Hydroxygrappe of the ethylidene intermediate A by oxidation and subsequent reduction with Metal hydride with formation of a II /? - hydroxyethylidene intermediate B cpimerized. This latter can form a mixture of a 17,20 diol C and a 17,20-ketol D are osmoylated. Optionally, the 11 / i-hydroxy group of the ethylenic intermediate product protected, for example by acetylation to form E, and subsequently are osmoylated, again to form a mixture of a 17.20 Dio! F and a 17,20 ketol G. The 20-oxo group of the ketol G can be protected by reaction with the formation of H, so that the acetoxy group at the 11-position to the ll / J-Hydro \ y-Z \ v; chemical product can be hydrolyzed can. This ketal can then be subjected to the Birch reduction and the reduction product under BiI-

Formation of 13 ^ -ethyl-II / ?, 17 \ -dihydroxy-18,19-dinorpregn-4-en-3,20-dione J hydrolyzed.

This key intermediate is reacted with pyrrolidine to form the enamine K, which is converted into its hydrochloride salt and brominated to form the 21-bromenamine salt L, whose Reaction with an acetate is IS-homo - ^ - norcortisol-21-acetate M yields, further hydrolysis of the same yielding 18-homo-19-norcortisol N. Optional the intermediate product K is reacted as a salt with lead tetraacetate with immediate formation of M.

It is clear to the steroid chemist that the reaction steps indicated above can also be carried out on compounds in which R ¹ does not contain any

Ethyl group, but a methyl or n-propyl group is. Furthermore, a steroid chemist will not find it difficult to make numerous modifications of the reaction scheme given above, both in terms of the sequence the reaction stages, as well as the type of reaction and the reactants used; this Process variants are obvious equivalents of the reaction sequences described above.

The steroid skeleton of the pentaoxylated Pregnens can be substituted in any position and by any substituent known to the steroid chemist. For example, the steroid skeleton can be used in 13-position by a n-alkyl group having ¹ · bi to 3 carbon atoms, namely methyl,

Ethyl or n-propyl group can be substituted. The oxylated function at the 11-position in the final product is suitably hydroxy, acyloxy. Alkoxy or oxo group. Although the hydroxy, acyloxy, or alkoxy groups can be in either the \ or /? Configuration, it is pre-weighed to have the / 3 configuration. The oxygenated function in 3-position is preferably an oxo group which is linked to a 4 (5) double bond in ring A, but it can also be used, for. B. be an enol ester or enol ether group, which can be connected to one or two double bonds in different positions in ring A and B. The oxygenated function in the 17-position is suitably a hydroxy, acyloxy or alkoxy group; this group preferably has a «configuration. The oxygenated function in the 20-position is preferably an oxo group, while that in the 21-position is preferably a hydroxyl, acyloxy or alkoxy group. In addition to the substituents given above, the nucleus can also be substituted in a number of other positions, for example the 1-, 2-, 4-, 6-, 7-, 9- and 16-positions. Examples of suitable substituents are alkyl groups, especially in the 6- and 7-positions, for example methyl groups, halogen atoms, for example fluorine and chlorine, alkyl groups and formyl groups. The ring D can also be a D-homologated ring.
If any of the above groups have a

Is or contains an acyl group, it is preferably cine aliphatic or aromatic carboxylacyl group with up to 20 carbon atoms; Examples of suitable ones Acyl groups are acetyl, propionyl, phenylacetyl, / Ϊ-phenylpropionyl and benzoyl groups. When a of the above groups is or contains an alkoxy group, it is preferably a methoxy, ethoxy, Tetrahydropyranyloxy, methoxy methoxy or dihydroxypyropylcxy group.

In the product of a total synthesis that does not include a suitable separation step, those after above processes produced compounds having the 130 configuration as equimolecular Mixture or in the form of a racemate with the corresponding 13a enantiomers, as in most of the the following examples are available. The racemates are determined according to the Horeau-Reichstein Convention (Fieser and Fieser, Steroide (1959), p. 336) referred to as (dl) -130 compounds, so that the enantiomer of the 130 configuration be the d-shape and Antipode, the enantiomer of the 13 »configuration, the 1-130 form and the racemate the dl-130 or (±) -l30 connection is. It is preferred to manufacture of d compounds to use d starting materials.

The pharmaceutical preparations which contain the process products according to the invention can in liquid or solid forms, for example capsules, tablets, suppositories, powders, dispersible Granules, lozenges, and the like, by combining them with conventional carriers, be formulated. Such conventional carriers include, for example, magnesium carbonate or Stearate, talk. Sugar, lactose, pectin, dextrin, starch. Gelatine, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low-melting wax and cocoa butter, diluents or extenders, flavor-forming substances, solubilizers, Lubricants, suspending agents, binders or tablet-disintegrating agents can also be used will. Powders and tablets preferably contain 5 or 10 to 99% active ingredient. The effective one Steroid can be presented with an encapsulating material, with or without a carrier.

Liquid preparations such as solutions, suspensions and emulsions can also be used. Such preparations include dispersions in a pharmaceutically acceptable carrier such as arachis oil or sterile water, preferably with a nonionic surfactant such as fatty acid esters or polyhydroxy compounds, e.g. B. sorbitan (for example polyethylene oxide fatty acid esters such as Tween 80), aqueous starch in sodium carboxymethyl cellulose solutions, aqueous propylene glycol solution. Such solutions can be used for parenteral injection can be used, and aqueous suspensions suitable for oral use can be made by using natural or synthetic gums, resins, methyl cellulose or other known suspending agents getting produced.

The compounds can be presented in the form of a unit dose, the unit dose being for example from 1 to 200 mg for each effective steroid, depending on the therapeutic desired Type, is. The unit dose form can be a packaged preparation, e.g. B. packaged powder, vials or ampoules, or for example in the form of pots. Lozenges or tablets any number of which be in packaged form. The pharmaceutical preparations can also essentially consist of the active steroid only if it can be used in unit dose form.

The invention is illustrated by the following examples. In these the temperatures are given in ⁰ C; the infrared absorption data (IR) relate to the position of the maxima indicated in cm- 'and the ultraviolet absorption data (UV)

ίο refer to the position of the specified in ΐημ Maxima, where the numerical values given in brackets represent the molecular extinction coefficients specify these wavelengths.

B e i s ρ i e 1 1

dI-13 /? - ethyl-3-methoxy-18,19-dinor-17 <x-pregna-1,3,5 (10) -triene-1,1 *, 1,7β-diol

ao l, 3.5 (lO), 9 (llj-tetraen-170-ol (6.5 g) was in dry Tetrahydrofuran treated under dry nitrogen with diborane, which is separated from sodium borohydride (9.33 g) in diglyme (300 ml) and boron trifluoride etherate (41.2 ml) in diglyme (100 ml).

The solution was allowed to stand at room temperature for 24 hours, followed by caution first Water (6 ml), then sodium hydroxide (14 g) in water (100 ml) and hydrogen peroxide (100 ml, 30%) were added. The solution was refluxed for 20 min.

heated for a long time, cooled and the organic layer removed. The aqueous layer was washed with tetrahydrofuran (200 ml), the combined organic layers washed with brine until neutral and then dried (MgSO ₁ ). Filtration and

tight in vacuo gave an oil that was absorbed over Florisil (280 g) and with an ether gradient in Benzene was eluted to give two crystalline fractions. The first fraction (5.09 g) became out Acetone / petroleum ether (40/60) to give the title compound (3.116 g) recrystallized; Melting point 165 to 166 °. The mother liquors gave a further 0.92 g, Melting point 173 to 175 ° (overall yield 59%).

Analysis for Cj ₂ H ₈₂ O ₈ :

Calculated
found .

C 76.70, H 9.36%,
C 76.71, H 9.33%.

Example 2

dl-130-ethyl-l 1 ic-acetoxy-3-methoxy-18,19-dinor-l 7a: -pregna-l, 3,5 (10) -triene-l 7/9-ol

dl-13 / S-ethyl-3-methoxy-18,19-dinor-17 "-pregnal, 3,5 (10) -triene-IIIa, 170-diol (18.62 g) in dry pyridine (140 ml) and acetic anhydride (270 ml) were held at room temperature for 16 hours.

The reaction mixture was poured into ice / water and solid sodium bicarbonate was poured into the mixture until the evolution of gas ceased. The crude product was extracted with ether, washed with 10 ° / ₀ hydrochloric acid, aqueous sodium bicarbonate, water, brine and dried (MgSO _4). Evaporation of the ether and recrystallization of the solid residue from methanol gave the title compound (15.97 g, 76.5%). Melting point 170 to 171 "; IR: 3528 (OH).

Analysis for C ₂₄ H ₃₄ O ₄ :

Calculated
found .

C 74.57, H 8.87%;
C 74.52, H 8.76%.

609 615-54

/ it

Example 3

dl-13 /? - ethyl-3-methoxy-l 1 α-acetoxy-18,19-dinorpregna-l, 3,5 (10), 17 (20) -tetraene

dl-13 / J-Ethyl-II "-acetoxy-3-methoxy-18,19-dinor-17" -pregna-1,3,5 (10) -trien-17y? -ol (5.12 g) in Dry pyridine (50 ml) was treated at -5 "with redistilled thionyl chloride (1.66 g, 1.01 ml) for 12 min. The mixture was stirred at -5 ° for an additional 15 min and then poured onto crushed ice. The crude product was extracted with ether, washed four times with dilute hydrochloric acid, aqueous sodium bicarbonate, brine, dried (MgSO ₄ ) and concentrated to an amber resin (4.26 g) Thin layer chromatography showed that the product still had some starting material Chromatography on a Florisil column (100 g) with elution with 2% acetone petroleum ether gave a homogeneous (thin layer chromatography) material in the form of a colorless glass (3.5 g, 72%). QFl at 185 °) showed a peak with a slight diffraction at the leading edge.

Analysis for C ₂₄ H ₃₂ O ₃ :

Calculated ... C 78.22, H 8.75%; found .... C 78.64, H 8.82%.

The product was crystallized in petroleum ether (40/60) and obtained after twice Recrystallize the title compound, melting point 97-101 °; IR: 1730, UV: 277 (1928).

Example 4

dm / S-EthyW-methoxy-lS. ^ - dinorpregnal, 3,5 (10), 17 (20) -tetraen-ll "-ol

dl-13 /? - ethyl-3-methoxy-lla-acetoxypregna-l, 3, -5 (10), 17 (20) -tetraene (1.264 g), potassium hydroxide (0.5 g), methanol (15 ml) , Tetrahydrofuran (10 ml) and water (10 ml) were refluxed under nitrogen for 1 hour. The resulting solution was evaporated to a small volume and extracted with ether. The combined ethereal extracts were washed with water and brine, dried (MgSO ₄ ) and concentrated to a colorless resin (1.02 g) which was isolated from a trace of starting material by absorption on a Florisil column (30 g) and eluting at 10 ° / ₀ strength acetone petroleum ether was freed, with formation of a homogeneous (thin layer chromatography) colorless resin of the title compound (790 mg, 71%) UV: 277 (1810).

Analysis for C ₂ JH ₃₀ O ₂ :

Calculated ... C 80.93, H 9.26%; found .... C 80.75, H 9.28%.

A sample crystallized from methanol had a melting point of 96 to 98 °.

Example 5

dl-13/9-ethyl-3-methoxy-l 8,19-di norpregna-2,5 (10), 17 (20) -triene-ll "-ol

dl-13/9-ethyl-3-methoxy-18,19-dinorpregna-1,3, -5 (10), 17 (20) -tetraen-lla-ol (2.01g) in tert.-butanol [25 ml), tetrahydrofuran (25 ml) and dry redistilled liquid ammonia (100 ml) were treated with lithium (0.299 g) under nitrogen. The blue solution was stirred for 40 min and then methanol (10 ml) was added. The ammonia was evaporated in a stream of nitrogen at 40 °. The resulting solution was diluted with tetrahydrofuran and washed with brine until the washings were neutral. After drying (MgSO ₄ ) and evaporation in vacuo, an oil remained, which crystallized from methanol gave the title compound (818 mg); Melting point 125 to 128 °. Several recrystallizations raised the melting point to 138 ° to 141 °.

Example 6

dl-D / J-Ethyl-ie.W-dinorpregna-4,17 (20) -diene-l 1 a-ol-3-one

dl-13i9-ethyl-3-methoxy-18,19-dinorpregna-2,5 (10), 17 (20) -triene-II * -ol (1.5 g) in methanol 50 ml) and tetrahydrofuran (50 ml ) were treated with hydrochloric acid (2 ml, 50%) and the solution heated under reflux under nitrogen for 30 min. Sodium bicarbonate was then added until the evolution of gas ceased. The organic layer was washed with brine and then dried (MgSO ₄ ). Filtration and evaporation in vacuo gave an oil which was absorbed on Florisil (70 g) and eluted with a step gradient acetone in petroleum ether (1 to 10%) to give a crystalline solid of the title compound (1.0 g); Melting point 162 to 166. Several recrystallizations from acetone / petroleum ether raised the melting point to 167.5 to 170 '.

Example 7

dl-13 /? - ethyl-18,19-dinorpregna-4,17 (20) -diene-11 * -ol-3-one, ethylene ketal

dl - ttß - ethyl -18.19 - dinorpregna - 4.17 (20) - dienll * -ol-3-one (1.7 g) in benzene (75 ml) and ethylene glycol (10 ml) were treated with p-toluenesulfonic acid (0.5 g) and the solution refluxed for 20 hours using a Dean and Stark water separator. The solution was then poured into saturated potassium carbonate solution (excess). The organic layer was washed with brine and then dried (MgSO ₄ ). Filtration and evaporation in vacuo gave a residue which was recrystallized from ethanol containing a trace of pyridine to give the title compound.

Example 8

dl-13 / S-ethyl-18,19-dinorpregna-4,17 (20) -diene-3,1 l-dione, 3-ethylene ketal

dl - Uß - ethyl -18.19 - dinorpregna - 4.17 (20) - dienll «-ol-3-one, ethylene ketal (2.1g) in pyridine (20 ml) is added to the reaction mixture, which consists of chromium trioxide (2 g) and pyridine (40 ml) and the mixture was allowed to stand overnight. It was then poured into excess saturated potassium carbonate solution, distilled with steam for 30 minutes and then extracted with ethyl acetate. The extracts were washed with brine and then dried (MgSO ₄ ). Filtration and evaporation in vacuo gave an oil which crystallized upon treatment with methanol. Recrystallization from acetone / petroleum ether gave the title compound.

35

45

55

60

65

Example 9

dl-13/3-ethyl-18,19-dinorpregna-4,17 (20) -dien-110-ol-3-one, ethylene ketal

dl - 13j9 - ethyl -18.19 - dinorpregna - 4.17 (20) - diene-3,11-dione, 3-ethylene ketal (1.40 g) in ethanol (50 ml) and water (2 ml) were with Treated sodium borohydride (1.5 g) and left to stand at room temperature for 5 hours. Excess 5N hydrochloric acid was carefully added and the mixture was heated under reflux for 30 minutes. Excess potassium carbonate solution was then added and the mixture extracted with ether. The extracts were washed with brine and then dried (MgSO ₄ ). Filtration and evaporation in vacuo gave an oil which crystallized after trituration with acetone. Recrystallization from acetone gave the title compound, melting point 155 ° to 161 °.

Example 10

dl-D / J-EthylO-methoxy-IS ^ -dinorpregna-2,5 (10), 17 (20) -trien-II-one and dl-13/3-ethyl-18,19-dinoφregna-4,17 (20) -dien-II / 3-ol-3-one

dl -13 / 3-ethyl-3-methoxy -18.19-dinorpregna-2.5 (10), 17 (20) -triene-II * -ol (0.546 g) in dimethyl sulfoxide (10 ml) and pyridine (0.137 ml) was treated with dicyclohexylcarbodiimide (719 mg) and trifluoroacetic acid (0.06 ml) and the mixture was left to stand at room temperature for 2 days. The precipitated dicyclohexylurea was removed by filtration and the filtrate was washed with phosphate buffer solution (pH 7.5), water and brine and then dried (MgSO ₄ ); Filtration and evaporation in vacuo gave an oil, a portion of which was washed with ice-cold hexane (2 to 20 ml) to give a light yellow solid, dm-EthyW-methoxy-IS. ^ - dinorpregna-2.5 (10), 17 (20 ) -trien-II-one was washed. The residue of the reaction mixture in ethanol (20 ml) and tetrahydrofuran (5 ml) was treated with sodium borohydride (515 mg) and allowed to stand at room temperature for 5 hours. Excess acetic acid was added, the mixture extracted with ether, the extracts washed with potassium bicarbonate solution and brine and dried (MgSO ₄ ). Filtration and evaporation in vacuo left a semi-solid, crystalline solid which was chromatographed on Florisil (30 g) using a step gradient of acetone in petroleum ether (0-10%). A crystalline solid (70 mg) was obtained which was recrystallized from acetone / petroleum ether, dl - 13 /? Yielded ethyl-18.19-dinorpregna-4,17 (20) -dien-II / 3-ol-3-one; Melting point 155 to 160 °.

Example Il

dl-D / S-ethyl-llß-acetoxy-HS ^ -dinorpregna-4,17 (20) -dien-3-one

dl -13/3 - ethyl -18.19 - dinorpregna - 4.17 (20) - dienll / 3-ol-3-one (1.2 g) in pyridine (4 ml) and acetic anhydride (8 ml) was over at room temperature Left for the night. The solution was then poured onto crushed ice with excess solid Treated sodium bicarbonate and extracted with ether, the extracts washed with brine and over Dried magnesium sulfate. Filtration and evaporation in vacuo left an oil which emerged Acetone / petroleum ether was recrystallized to give the title compound.

Example 12

dl-1 3ß-Ä thy 1-11 α-acetoxy-l 8,19-di norpregna-4,17 (20) -dien-3-one

dl -13/3 - ethyl -18.19 - dinorpregna - 4.17 (20) - dienll-x-ol-3-one (623 mg) in pyridine (2 ml) and acetic anhydride (4 ml) was over at room temperature Left for the night. The solution was then poured onto crushed ice with excess solid Treated sodium bicarbonate, extracted with ether, the extracts washed with brine and dried over Dried magnesium sulfate. Filtration and evaporation in vacuo left an oil which was removed Recrystallized acetone / petroleum ether to give the title compound (569 mg); Melting point 117 to 120 °.

B ei s ρ i e 1 13

dl-13/3-ethyl-l 1 a-acetoxy-3-methoxy-18,19-dinorpregna-1,3,5- (10) -trien-17 * -ol-20-one

Triethyl minoxide peroxide (1.46 g, 9.6 mM) was added in small portions over the course of 2 days to a solution of dl-13/3-ethyl-II * -acetoxy-3-methoxy-18,19-dinorpregna- 1,3,5- (10), 17 (20) -tetraene (482 mg) (1.3ImM) and osmium tetroxide (15 mg) in pyridine (0.4 ml) and tert-butanol (25 ml) were added. The solution was then stirred with an excess of aqueous sodium sulfite for 5 minutes and carefully extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO ₄ ) and evaporated to a dark brown semi-solid mass (542 mg), the latter was eluted on a Florisil column (30 g). 12% acetone / petroleum ether gave the title compound (167 mg, 32%) which, after recrystallization from aqueous methanol, had a melting point of 211 to 215 °. IR: 1720, 1710.

Analysis for C ₂₄ H ₃₂ O ₅ :

Calculated
found .

C 71.97, H 8.05%; C 71.54, H 8.34%.

Examples

dl-13/3-Ethy 1-11 a-acetoxy-20,20-ethylenedioxy-3-methoxy-18,19-dinorpregna-1,3,5 (10) -trien-17a-ol

A solution of dl-13/3-ethyl-ll «-acetoxy-3-methoxy-18.19-dinorpregna -1,3,5 (10) -triene-17a-ol-20-one (1.87 g) and p-toluenesulfonic acid monohydrate (300 mg) in benzene (100 ml.) with ethylene glycol was stirred and refluxed using a water separator for 16 hours. The cooled mixture was poured into water, the benzene layer separated and washed with aqueous potassium bicarbonate, then with brine, dried (MgSO ₄ ) and evaporated to dryness. The solid residue obtained was recrystallized from ethyl acetate containing one drop of pyridine to give the title compound; (1.55g, 75%); Melting point 194 to 196 °; UV: 277 (1915).

! 6 43 618 - _'38

Vl w coherence with a solution of sodium

³⁷ nitrogen atmosphere _{methanol (20 ml) and water gr}

B is ρ ie 1 15 ^metab , is poured into water and treated with methylene

(20 ml) heated in _{extracts were dissolved with salt}

-uirti-iil extranicn · «^ r?: _ ^"mr> f ".n _o ; n Λι j.

(
dll ^^^ J ^ _{1leil7 () H} Chloride j _{eech Eindap n Q} J

18,19-dinorpregna-l, 3,5 (10) _{tons of} washed ^^^ _and the solid obtained

i. nfi Äthvl-Ha-acetoxy-20,20-ethylenedioxy chromatograph "^ _{ista" ized are obtained |}

One received the

^ _n -11 «17«, 21 tno ^ _imethylsu i _fox id (17.5 ml),

? S2mW ^ ^tur S! ' ^It ^

ii-xl7 «-diol- ao long at Kaumi / <0ml) added and the stirring

added and the * 7 ^ * Ä,% Me example »

under ^ ™ "^"'^"extra-«<* ⁶ Jf ₅ ^ Tu given the solution obtained

Formation of the title compound (2 \ mg 28 /) around _hn , ggc ^ ^ _1ΗΜΐϊ οη des produ

siert; Melting point 210 to 213, UV. IAiK ^ Ä-Hexane one got the title compound.

^{Example 117} , Example 20

A solution to ""

in a «

Example 21 dl-13 /? - Ethyl-20,20-ethylenedioxy-3-methoxy-

lla, 21-diacetate

dl - 13 /? - Ethyl - 3 - methoxy - 18.19 - dinorpregna-1,3,5 (10) - triene -11 ", 17", 21 - triol - 20 - one, ll, 21 - diacetate (1.8 g), p-Toluenesulfonic acid, ethylene glycol (6 ml) and benzene were refluxed with a Dean-Stark water separator for 16 hours. heated for a long time. Then water was added to the mixture, the benzene layer separated, washed with saturated aqueous potassium bicarbonate, dried (MgSO ₄ ) and evaporated to a resin. This was evaporated off under vacuum. The crystalline residue was then recrystallized from acetone-hexane. The desired title compound was obtained in this way.

Example 25

dl-13 /? - ethyl-III-acetoxy-18,19-dinorpregn-4-en-17, -ol-3,20-dione

dl -13 /? - ethyl- IU -acetoxy-18,19 - dinorpregna-4,17 (20) -dien-3-one (100 mg) in tert-butanol (20 ml) was mixed with osmium tetroxide (15 mg) in tert-butanol (0.4 ml) and N-methylmorpholine-N-oxide-hydrogen peroxide complex (212 mg; 80% active peroxide; 2.5 molar equivalents) treated, and the resulting

Ethyl acetate, which contained a drop of pyridine, was dissolved at 37 ° under a nitrogen atmosphere

crystallized, and the title compound was obtained. Example 22

25th

ßyy
18,19-dinorpregna-l, 3,5 (10) -triene-lla, 17ft, 21-triol

13 - ethyl - 20.20 - ethylenedioxy - 3 - methoxy-18.19 - dinorpregna -1.3.5 (10) - triene - 11 ^, 17λγ, 21 - triol, ll *, 21-diacetate (0.5 g) in tetrahydrofuran (50 ml), methanol (20 ml) and water (5 ml) with potassium hydroxide (0.2 g) was heated to reflux under nitrogen for 1 hour. After evaporation of the solvent the residue was taken up in methylene chloride in vacuo and washed with water and evaporated to a colorless resin. This was then recrystallized from methanol, and one received the title connection. Stirred for 19 hours. The solution was then poured into excess, Poured saturated aqueous sodium sulfite and extracted with methylene chloride. The extracts were washed with brine and dried over magnesium sulfate. Filtration and Evaporation in vacuo gave an oil. Preparative thin layer chromatography over silica gel revealed three factions. The main amount was recrystallized from methanol. The title compound was obtained (28 mg).

Example 26

dl-13 /? - ethyl-18,19-dinorpregn-4-en-lla, 17a-diol-3,20-dione

Example 23

dl-13 /? - ethyl-18,19-dinorpregn-4-en-l l *, 17 *, 21-triol-3,20-dione

Lithium (450 mg) became dl-13 /? - ethyl-2O, 2O-ethylenedioxy - 3 - methoxy - 18.19 - dinorpregna - 1,3,5 - (] 0) -triene-lla, 17 ^, 21 -triol (120 mg) in redistilled, liquid ammonia (100 ml) and 1-methoxypropane-2-oil (15 ml) were added over the course of 45 minutes. Methanol (7 ml) was then added to the mixture and the ammonia evaporated. After adding water, the crude product was extracted with methylene chloride, washed with brine and evaporated to a crystalline residue. This was taken up in methanol (15 ml) and treated with 10% v / v under nitrogen for 1 hour. aqueous sulfuric acid (1.5 ml) heated to reflux. Most of the methanol was evaporated in vacuo, the solid residue extracted into ethyl acetate, washed with aqueous potassium bicarbonate, dried (MgSO ₄ ) and evaporated to dryness. The fixed dl -13 /? - Ethyl -IU- acetoxy -18.19 - dinorpregn-4-en-17 «-ol-3,20-dione (25 mg) in ethanol (10 ml) was mixed with sodium hydroxide (50 mg) in ethanol (5 ml) and water (5 ml) and the heated solution under reflux in a nitrogen atmosphere for 1 hour.

heated for a long time. Most of the solvent was removed under vacuum and the remaining solution poured into water and extracted with methylene chloride. The extracts were washed with water until neutral and then dried (MgSO ₄ ).

Filtration and evaporation of the solvents in vacuo gave a solid which recrystallized from acetone gave the title compound (17 mg).

Example 27

dl-13 ^ -Ethyl-IIA-acetoxy-17 «, 20a-epoxy-18,19-dinorpregn-4-en-3-one

dl -13 /? - Ethyl -11 «- acetoxy -18.19 - dinorpregna-4,17 (20) -dien-3-one (607 mg) in ether (10 ml) was mixed with a solution of monoperphthalic acid in ether ( 51.5 ml, 12.1 g / l) and the solution left to stand at 0 ° overnight. The solution was washed with 2N sodium hydroxide and brine and then dried (MgSO ₄ ). Filter and evaporate

The residue was then recrystallized from ethyl acetate, 55 in vacuo gave a solid, which was obtained from ether / and the title compound was obtained. Petroleum ether recrystallizes the title compound

(424 mg).
Example 24 Example 28

8,19-dinorpregn-4-en-17a, 21-diol- _6o dl-l ^ S-ethyl-llot-acetoxy-lS.lQ-dinorpregn-

3,11,20-trione, 4-en-17a-ol-3,20-dione

A slight excess of Jones reagent (8n-chromic acid) was converted into dl-13 /? - ethyl-18,19-dinorpregn-4-en-ll ", 17", 21-triol-3,20-di-one ( 70 mg) in acetone (3 ml. After 15 min. At room temperature an excess of isopropanol was added, then ice water and the product was then extracted in ethyl acetate, washed, dried (MgSO ₄ ) and dl-13 ^ -ethyl-II « -acetoxy-17 ", 20" -epoxy-18,19-dinorpregn-4-en-3-one (100 mg) in dimethyl sulfoxide (10 ml) was heated at about 90 ° on a hot water bath for 24 hours, with steady Air was bubbled through the solution, the solution was then poured into water and extracted with methylene chloride, the extracts washed with water and washed over

Dried magnesium sulfate. Filtration and evaporation in vacuo gave an oil which was triturated crystallized out with methanol. Recrystallization gave the title compound (27 mg).

Example 29

dl-O / S-ethyl-lla-acetoxy-lS.l ^ dinorpregn-4-en-17 ", 20 £ -diol-3-one

norpregn-4-en-3-one (20 mg) in acetone (2 ml) was treated with 7% aqueous perchloric acid (0.1 ml) and let the solution stand overnight. Solid sodium bicarbonate and magnesium sulfate were made admitted. Filtration and evaporation in vacuo gave a solid consisting of acctone petroleum ether was recrystallized; the title compound (17 mg) was obtained.

B e 1 s ρ 1 e 1 30

dl-lS / S-ethyl-lla-acetoxy-lS. ^ - dinorpregn-4-en-17a-ol-3,20-dione

(4 ml) and N-methylmorpholine-N-oxide-hydrogen peroxide (283 mg; 68% active peroxide) and the solution was stirred under nitrogen for 2 ¹ I for ₂ hours. The solution was poured into saturated sodium sulfite solution and extracted with methylene chloride. The extracts were washed with water and dried (MgSO ₄ ). Filtration and evaporation in vacuo gave a resin which was chromatographed on Florisil (15 g) using a gradient of 1 to 25% acetone in methylene chloride. The main fraction so obtained was recrystallized from acetone to give the title compound (84 mg).

-J-on (50 mg) in dimethyl sulfoxide (5 ml) dd

Example 34

^dl - ¹ - ³ P-ethyl-18,19-dinorpregn-4-en-ll *, 17 ", 21-tnol-3,20-dione

«» - ^ Ethyl-lla-acetoxy-ie.lQ-dinorpregiM-en-17 _Ä , 21-diol-3,20-dione (213 mg) in tetrahydrofuran (20 ml) and ethanol (20 ml) was ^{treated with sodium hydroxide (100%)} mg) in water (2 ml) and ethanol (5 ml) and the solution is heated under reflux in a nitrogen atmosphere for 1V for ₂ hours. The solvent was removed in vacuo and the residue i W

) m away and the back

was treated with acetic anhydride (2.5 ml) and * 5 was poured into water and treated with methylene chloride the solution is extracted overnight at room temperature. The extracts were washed with water

and dried (MgSO ₄ ). Filtration and evaporation in vacuo yielded a solid which, after recrystallization A

calmly. It was poured into excess potassium bicarbonate solution and extracted with methylene chloride. The extracts were washed with water and dried (MgSO ₄ ) filtration and evaporation 30 (152 mg).

in vacuo left a solid which was recrystallized from acetone and the title compound (33 mg).

Eg game 31

dm / J-Ethyl-lla-acetoxy ^ O / S-tosyloxy-18,19-dinorpregn-4-en-17a-ol-3-one

dl-13 ^ Ethyl-ll _a -acetoxy-18,19-dino _rp regn-4-en-17 _a , 20 ^ diol-3-one (77 mg) in carbon tetrachloride (20 ml) was treated with p-toluenesulphonyl chloride (42 mg; 4 «1.2 equivalent) and the solution left to stand overnight. It was washed with sodium bicarbonate and dried (MgSO ₄ ). Filtration and n a solid after Um

the title compound crystallize from acetone (152 mg) itelverbmdung ergaq

B e i s r> i e 1

G
3,11,20-trione

^{dl "13/3:} ethyl lS, 19-dinorpregn-4-en-llix, 17", 21-triol-3,20-dione (183 mg) in pyridine (5 ml) was treated with a

The SShT H ^U ? ^r _r ^ T
£ ngeeosLn u ^ dti, M, hT ί ™ ^blCarb ° ^na 'Di ^^ IxSte were "X 7 fi ^ -

Di ^^

" ^stopped

^sati0 "

For example _{P iel32}

l ^ acetoxy-lSa
4,20-diene-17 "-ol-3-one

^Bei P ^{iel 36}

⁵ °

dl-13 /? - ethyl-ll "-acet _O xy-20 ^ tosyloxy-18,19-dinorpregn-4-en-17 _{a-ol-3- O} n (52 mg) in Acel 20 ml) was treated with sodium acetate (100 mg) and the suspension is heated under reflux for 2V, hours. FiI- . / 1 ° ^{ml (} ? ⁸

(28 mg).

. Example 33

dl-Djff-Ethyl-lla-acetoxy-lS.lP-dinorpregn-4-en-17 «, 21-diol-3,20-dione

I-II _Ä -acetoxy-18,19-dinorpregna-4,20- (179 mg) in tert, ButTnol (20 ml) was poured with osmium tetroxide (15 mg) in tert-butanol and extracted with methylene chloride. ? ^ie ^ ™} ?? * ^{Are washed with} water and dried (MgSO ₄ ). Filtration and evaporation in vacuo gave an oil which was dissolved in ethanol (30 ml) ^and water (2 ml) and treated with concentrated salt
heated. The Ä S ?

Äe TcS de? Solution
Vacuum removed and the verbSn ^ e V

Poured potassium bicarbonate solution and extracted with methylene chloride. The extracts were washed with water and dried (MgSO ₄ ). Filtration and evaporation in vacuo gave an oil. This was chromatographed on Florisil (30 g) using a gradient of 1 to 15% acetone in methylene chloride. Recrystallization of the main component from acetone gave the title compound (73 mg).

Example 37

dl-13) 3-Ethyl-II /? - acetoxy-18,19-dinorpregn-4-en-17a-ol-3,20-dione

(20) -dien-3-one (100 mg) in tert-butanol (20 ml) was with osmium tetroxide (15 mg) in tert-butanol (0.4 ml) and N-methylmorpholine-N-oxide-hydrogen peroxide complex (212 mg; 80% active peroxide; 2.5 molar equivalents) treated and the resulting solution at Stirred at 37 ° under nitrogen for 19 hours. The solution was then saturated into excess aqueous Poured sodium sulfite and extracted with methylene chloride. The extracts were washed with brine and dried over magnesium sulfate. Filtration and evaporation in vacuo gave an oil. The preparative Thin layer chromatography on silica gel provided three fractions. The main faction was recrystallized from methanol to give the title compound.

Example 38

dl-13) 3-ethyl-18,19-dinorpregn-4-enll / 3,17ix, 21-triol-3,20-dione, ll, 21-di-acetate

dl-13 | 3-ethyl-18,19-dinorpregn-4-en-ll ^, 17ft-diol-3,20-dione-ll-acetate (400 mg) in methanol (5 ml) and peroxidic tetrahydrofuran (10 ml ) was stirred with calcium oxide (0.6 g) and iodine (0.6 g) at 25 ° for 2 hours. The mixture was diluted with methylene chloride and filtered. The filtrate was washed four times with 5% sodium thiosulfate, dried (MgSO ₄ ) and evaporated not less than 30 ° to give a resin. This latter was refluxed with freshly melted potassium acetate (0.7 g) in acetone (10 ml) for 16 hours. The mixture was evaporated at 30 ° and extracted with methylene chloride, the organic layer being washed with water, dried (MgSO ₄ ) and evaporated to a yellow resin. This resin was purified by eluting on a Florisil column with acetone-methylene chloride mixtures; the desired product thus obtained was recrystallized from acetone-hexane to obtain the title compound.

Example 39

⁵⁵

ll / ?, 17 * -21-triol-3,20-dione Recrystallized acetone gave the title compound (152 mg).

Example 40

dl-13 /? - ethyl-II / J, 17 ", 21-triacetoxy-18,19-dinorpregn-4-ene-3,20-dione

dl -13) 3 - ethyl -11) 3.21 - diacetoxy -18.19 - dinorpregn-4-en-17 «-ol-3,20-dione (470 mg) acetic anhydride (1 g) and p-toluenesulphonic acid hydrate ( 500 mg) in dry benzo '(50 ml) was refluxed using a Dean-Stark trap for 5 hours. The solution was then poured into water and extracted with ether. The extracts were washed with potassium bicarbonate solution and brine, then dried (MgSO ₄ ). Filtration and evaporation in vacuo gave a solid which recrystallized from ether / petroleum ether gave the title compound (320mg).

Example 41

dl-13j3-ethyl-l 8,19-dinorpregn-4-en-

11a, 17 ", 21-triplet-3,20-dione

13) 3 - ethyl - 21 - acetoxy -18.19 - dinorpregn - 4 - enlla, 17 <x-diol-3,20-dione (0.2 g) in methanol (100 ml) was mixed with potassium bicarbonate (0.4 g) in water (60 ml) Stirred for 18 hours in a nitrogen atmosphere. The mixture was extracted with chloroform and the organic layer was washed, dried and evaporated. The residue was made from acetone-hexane recrystallized to form the title compound.

4-en-17'-ol-3,20-dione (213 mg) in tetrahydrofuran (20 ml) and ethanol (20 ml) was treated with sodium hydroxide (100 mg) in water (2 ml) and ethanol (5 ml) ., the solution is heated and refluxed under nitrogen for I ¹ Z ₂ hours long. The solvent was removed in vacuo, the residue poured into water and extracted with methylene chloride. The extracts were washed with water and dried over magnesium sulfate. Filtration and evaporation in vacuo gave a solid which was

Example 42

dl-13 /? - ethyl-18,19-dinorpregn-4-enll) 3,17 * -diol-3,20-dione

To dl-13)? - ethyl-18,19-dinorpregna-4,17 (20) -dienll /? - ol-3-one (1 g) and osmium tetroxide (0.03 g) in pyridine (0.8 ml) and tert-butanol (50 ml) is triethylamine-hydrogen peroxide complex (1.9 g) added in small portions over 48 hours. The mixture is made with excess aqueous sodium sulfite Washed for 5 min. And then extracted with methylene chloride. The organic extracts are made washed, dried and evaporated to give a residue which was chromatographed on Florisil (100 g) would. Eluting with petroleum ether containing increasing proportions of acetone gave the title compound

Example 43

dl-13) 3-ethyl-21-acetoxy-18,19-dinorpregn-4-enII / 3,17 «-diol-3,20-dione

dl-13 /? - ethyl-18,19-dinorpregn-4-en-ll _l 6, 17 "-diol 3,20-dione (0.5 g) in methanol (2 ml) and tetrahydrofuran (3.5 ml) containing azobisisobutyronitrile (35 mg) is stirred with calcium oxide (0.6 g) and iodine (0.6 g for 2 hours at 25 °. After dilution with methylene chloride and filtration, the aqueous filtrate is washed with aqueous sodium thiosulphate and The water is washed and dried, the solvent is evaporated at 25 ° C. and the residue is refluxed with water free potassium acetate (0.8 g) in acetone (10 ml) for 16 hours. The solvent is evaporated at 25 °, and water becomes and the mixture is extracted with methylene chloride, the organic extract is washed, dried and evaporated and the residue is chromatographed on Florisil

Phiert, eluted with hexane-ether mixtures, gave the title compound.

Example 44

II / 9.17 ", 21-triol-3,20-dione

dl-13 / S-ethyl-21-acetoxy-18,19-dinorpregn-4-enII / 9,17 "-diol-3,20-dione (0.2 g) in methanol (100 ml) is mixed with potassium bicarbonate (0.4 g) in water (60 ml) Stirred for 18 hours in a nitrogen atmosphere. The mixture is extracted with chloroform and the organic solution washed, dried and evaporated. Recrystallize the residue from acetone-hexane gave the title compound.

Example 45

dl-lS / S-ethyl-II / Y-acetoxy-.l-methoxy-lS.ig-dinorpregna-l, 3,5 (10) -trien-17a, 20/3-diol

It was dl-lla-acetoxy-D / S-ethyl-S-methoxy-18,19-dinorpregna-l, 3.5 (10), 17 (20) -tetraene (2.85 g) in tetrahydrofuran (50 ml ) and pyridine (5 ml) are treated with osmium tetroxide (2 g) in tert-butanol (25 ml) and the mixture is left to stand at 25 ° for 72 hours. The solution was saturated with hydrogen sulfide and the precipitate was filtered off. The filtrate was evaporated and the residue was eluted on Florisil (50 g) chromatographs and with petroleum ether-acetone (9: 1) to remove starting material. It was eluted with acetone to give a light brown solid. Recrystallization from methanol gave the title compound (1.84 g), m.p. 258-265 ^r .

Example 46

dl-ll ^ O / '- Diacetoxy-Dß-ethyl-nft-hydroxy-3-methoxy-18,19-dinorpregna-1,3,5 (10) -triene

Dl-ll \ -acetoxy-13 ^ -ethyl-17 «, 20-dihydroxy-3-methoxy-18,19-dinorpregna-1,3,5 (10) -triene was allowed Stand (0.104 g) in acetic anhydride (0.5 ml) and pyridine at 25 ° for 48 hours. Then it was in water poured, extracted with ether, washed, dried and the ethereal solution evaporated. Recrystallization of the product from methanol gave the title compound, melting point 185-189 °.

Example 47

dl-13 /? - Ethyl-II «, 17ix, 2O0-trihydroxy-3-methoxy-18,19-dinorpregna-1,3,5 (10) -triene

A solution of dI-lla-acetoxy-13fl-ethyl- n <\, 20ß - dihydroxy - 3 - methoxy -18.19 - dinorpregnal, 3.5 (10) -triene (0.208 g) with potassium hydroxide (0, 17 g) in tetrahydrofuran (15 ml), methanol (2 ml) and water (2 ml) IV _{heated to reflux for 2} hours under a nitrogen atmosphere. Most of the solvent was evaporated, methylene chloride was added, washed, dried and the solution evaporated to give the title compound (0.153 g). Recrystallization from methanol gave the pure compound, melting point 218.5 to 225 ^r

Analysis for C ₂₁ H _n O ₄ :

Calculated ... C 73.3, H 8.95%;
found .... C 73.14, H 9.17%.

Example 48

dl-ll _L \, 17 "-dihydroxy-13-ethyl-3-methoxy-

18.19-dinorpregna-1,3,5 (10) -trien-20-one
5

It became dl-13/3-ethyl-II «, 17 * -dihydroxy-3-methoxy-18,19-dinorpregna-1,3,5 (10) -trien-20-one-ethyl ketal (0.092 g) in methanol (7 ml) with 10% aqueous sulfuric acid (0.5 ml) for 40 min. At the re-must heated. Then water was added and extracted with methylene chloride. After washing, drying and evaporation of the organic extract and recrystallization from methanol to give the title compound (0.042 g), melting point 103-107 °.

Analysis for C ₂₂ H ₃₀ O ₄ CH ₃ OH:

Calculated
found .

C 70.74, H 8.78%;
C 70.89, H 8.71%.

Example 49

dl-3-Methoxy-13 /? - ethyl-18,19-dinorpregnal, 3,5 (10), 17 (20) -tetraen-II-one

Dicyclohexylcarbodiimide (3.8 g) was added to a solution of dl-3-methoxy-13 ^ -ethyl-18,19-dinorpregnal, 3,5 (iq), 17 (20) -tetraen-IV-> t-ol ( 2.0 g), pyridine (0.49 ml) and dichloroacetic acid (0.27 ml) were added and the mixture was stirred at 25 ° for 16 hours. Then ether (100 ml) followed by a solution of oxalic acid (1.65 g) in methanol (15 ml) was added and the mixture was stirred for an additional hour. Water was added, the mixture was filtered and the product was then isolated from the filtrate after washing with aqueous potassium bicarbonate and water and dried (MgSO ₄ ) by evaporating the semi-solid residue. This was then recrystallized from methanol, and the ketotetraene (1.52 g, 76%), melting point 152 to 154 ° ^{C., was obtained} . The analytical sample had a melting point of 154 to 157 ^r (from acetone-hydrogen). UV: 277 (1656), 284.5 (1552).

* Analysis for C ₂₂ H ₂₈ O ₂ :

Calculated
found .

C 81.44, H 8.70%;
C 81.50, H 8.88

O/

/O·

Example 50

dl-3-methoxy-13 / S-ethyl-18,19-dinorpregna-

l, 3.5 (10), 17 (20) -tetraen-II /? - ol

A solution of ketotetraene (1.5 g) from the previous example in tetrahydrofuran (50 ml) was added to a suspension of lithium aluminum hydric (3.0 g) in ether (100 ml) and the Gemiscl stirred under reflux for 1 hour. After careful! Addition of methanol and then water was carried out the mixture filtered, the filtrate dried and concentrated

steamed. The crystalline residue obtained was recrystallized from methanol, and there! Tetraenol (1.21 g, 81%), melting point 128-129.5 ° UV: 278 (1924). The analytical sample had an egg Melting point from 129 to 131 ° C (from methanol).

Analysis for C _n H ₃₀ O ₂ :

Calculated
found

C 80.93, H 9.26%;
C 81.06, H 9.16%.

Example 51

norpregna-l, 3.5 (10), 17 (20) -tetraene

A solution of the tetraenol (14.32 g) from the previous example and acetic anhydride (? 00 ml) in pyridine (100 ml) was heated at 100 ° for 2 hours and left to stand at 25 ° for 2 days. The mixture was poured onto ice and the product was then extracted with ether, washed with 2η hydrochloric acid, potassium bicarbonate and water, dried (MgSO ₄ ) and evaporated. The residue obtained in this way was recrystallized from methanol, and acetoxytetraene (13.3 g, 83%), melting point 159.5 ° to 161 °, was obtained. A second crop obtained from the mother liquors (1.0 g, 6.2%) had a melting point of 154-156 °. The analytical sample melted at 160 to 161 ° (from methanol). UV: 278 (1934), 286 (1882).

Analysis for C ₂₄ H ₃₂ O ,,:

Calculated
found .

C 78.22, H 8.75%;
C 77.94, H 8.74%.

Example 52

dl-11ß-acetoxy-na-hydroxy-S-methoxy-13/3-ethyl-18,19-dinorpregna-1,3,5 (10) -trien-20-one

N - methylmorpholine - N - hydrogen oxide peroxide complex (17.5 g) was converted into a solution of 11 /? - acetoxytetraene (13.3 g) from the previous example and _{in the course of 1/2 hour at 40 ° with stirring under nitrogen} Osmium tetroxide (450 mg) in pyridine (3 ml) and tert-butanol (310 ml) were added. After a further I ¹ I ₂ hours at 40 °, a 2% strength aqueous solution of sodium sulfite was added and the mixture was stirred overnight. The crude product was isolated by extraction with methylene chloride, washed with water and evaporated to a solid residue (14.35 g) which contained a major and two minor components. Eluting the reaction product on a Florisil column (300 g) with 1 to 2% acetone / methylene chloride gave a two-component mixture which, after recrystallization from methylene chloride-methanol, gave the partially solvated title ketol (6.76 g, 46%), melting point 155 to 174 °. The analytical sample had a melting point of 183 to 185 "(from acetone-hexane) UV: 278 (1960).

Analysis for Cj ₄ H ₃₁ O ₆ :

Calculated
found .

C 71.97, H 8.05%;
C 71.63, H 8.12%.

The methanol mother liquors given above slowly exposed crystals of the second component Formation after further crystallization from methanol of dl-llß-acetoxy-lS-ethyl ^ -methoxygona-l ^ .S- (10) -trien-17-one (413 mg, 3.2%), melting point 201-202.5 °.

Further elute the column with 5% acetone / methylene chloride and recrystallize the product Methanol gave dl-IIß-acetoxy-S-methoxy-13 /? - ethyl -18.19 - dinorpregna - i, 3.5 (10) - triene -17, \, 20/3 diol (2.61 g, 18%) m.p. 215 '. The ana-

The lytic sample had a melting point of 213 to 215 ° (from acetone-hexane). UV: 278 (1896).

Analysis for C ₂₄ H ₃₄ O ₅ :
Calculated ... C 71.61, H 8.51%;

found

C 71.67, H8.59 <.

Example 53

dl-11 / 3,17a-dihydroxy-3-methoxy-l 3/3-ethyl-18,19-dinorpregna-1,3,5 (10) -trien-20-one

N - methylmorpholine - N - hydrogen oxide peroxide complex was at 40 ° with stirring over the course of 2 hours to a solution of dlO-methoxy-IS / S-ethyl-18,19-dinorpregna-1, 3,5 (10), 17- (20) -tetraen-11/3-ol (2.96 g) and osmium tetroxide (60 mg) in tert-butanol (60 ml) and pyridine (0.8 ml) were added and the mixture stirred at 40 ° for a further 2 hours. The crude product was isolated as indicated above and by chromatography Purified on a Florisil column (160 g). Elute with 2% acetone-methylene chloride the ketodiol, which after recrystallization from methanol had a melting point of 202 to 206 ° (999 mg, 30.5%,). The analytical sample melted at 210 to 212 ° (from acetone-hexane). UV: 278 (1968), 286.5 (1902).

Analysis for C ₂₂ H ₃₀ O ₄ :

Calculated ... C 73.71, H 8.44%;
found .... C 73.74, H 8.37%.

Further elution of the column with acetone gave a second product after crystallization from Me ethanol from dlO-methoxy-IS / S-äthyl-ie ^ -dinorpregnal, 3,5 (10) -triene-II / 3,17,20 / 3-triol (362mg, 11%), melting point 211 to 216 °. The analytical sample melted at 217 to 219.5 ° (from acetone-hexane). UV: 278 (1917).

Analysis for C ₂₂ H ₃₂ O ₄ :

Calculated ... C 73.30, H 8.95%;
found .... C 73.14, H 9.03%.

B e i s ρ i e 1 54

dl-II / S-acetoxy ^ O ^ O-ethylenedioxy-S-methoxy-13/3-ethyI-18,19-dinorpregna-1,3,5 (10) -trien-17-ol

A solution of dl-llß-acetoxy-n-hydroxy -} - methoxy-13/3-ethyl-18,19-dinorpregna-1,3,5 (10) - trien-20-one (6.76 g) and p-toluenesulfonic acid monohydrate

(1.0 g) in benzene (600 ml) and ethylene glycol was refluxed for 24 hours while stirring with a Dean-Stark trap. The mixture was cooled, washed with water and aqueous sodium bicarbonate, dried (K ₂ CO ₃ ) and evaporated;

the ketal was obtained (7.0 g, 94.5%), melting point at 221 ° to 230 °. The analytical sample melted on 228 to 233 ° (from ethyl acetate); UV: 277 (1974).

Analysis for C _2e H _se O _e :

^fi o Calculated ... C 70.24, H 8.16%;
found .... C 70.25, H 8.08%.

Example 55

dl-20,20-ethylenedioxy-3-methoxy-13 /? - ethyl

18,19-dinorpregna-l, 3,5 (10) -triene-ll / ?, 17-diol

A solution of the ketal (7.0 g) from the previous example in tetrahydrofuran (300 ml) was made

to a stirred suspension of lithium aluminum hydride (4 g) in ether (300 ml) and the mixture stirred at 25 ° for 2 hours. Methanol-ether and then water were added and the mixture was filtered. The filtrate was dried (MgSO ₄ ) and evaporated to a solid residue. After recrystallization from ethyl acetate, this gave the title ketal (4.84 g, 76%), melting point 219 ° to 221 °. UV: 278 (1928).

Analysis for C ₂₄ H ₃₄ O ₅ :

Calculated ... C 71.61, H 8.51%;
found .... C 71.69, H 8.56%.

Example 56

dl-ll ^ n-dihydroxy-n / S-ethyl-lS.W-dinorpregn-4-en-3,20-dione

Lithium (11.7 g) was in small pieces in the course of IV ₂ hours to a solution of dl-20,20-ethylenedioxy - 3 - methoxy -13 / 3-ethyl -18.19 - dinorpregnal, 3.5 ( 10) -triene-II / 3,17-diol (4.84 g) in redistilled liquid ammonia (2.5 l), tetrahydrofuran (200 ml) and 1-methoxypropan-2-ol (400 ml) were added. The mixture was stirred for 16 hours, during which time most of the ammonia evaporated. Water was then added and the mixture extracted thoroughly with ethyl acetate. The combined extracts were washed with water, dried (Ks ₁ CO ₃ ) and evaporated to a crystalline residue (4.12 g). The latter was dissolved in tetrahydrofuran (100 ml) and methanol (200 ml), 10% aqueous sulfuric acid (20 ml) was added and the solution was then stirred under nitrogen at 25 ° for 16 hours. Most of the solvent was then evaporated in vacuo and the crude product extracted with ethyl acetate and evaporated to a solid residue (4.47 g). Recrystallization of the residue from ethyl acetate gave the title compound as a virtually insoluble fraction (1.98 g, 47%), melting point 259 ° to 261 °. UV: 243 (14,955).

Analysis for

Calculated
found .

C 72.80, H 8.73%;
C 72.88, H 8.65%.

Example 58

dl-II / 3-acetoxy-17-hydroxy-3-methoxy-13/3-ethyl-18,19-dinorpregna-1,3,5 (10) -trien-20-one

A solution of dl-II / S-acetoxy-3-methoxy-13/3-ethyl-18,19-dinorpregna-1,3,5 (10) -triene-17,20 /? - diol (124 mg) in Dimethyl sulfoxide (5 ml) and acetic anhydride (2.5 ml) were left at 25 ° for 16 hours. Water was then added, the product extracted with ether, washed with aqueous sodium bicarbonate, dried (MgSO ₄ ) and evaporated to an oil which slowly crystallized. Recrystallization of the crude product twice from acetone-hexane gave the almost pure dl-II / S-acetoxy-17-hydroxy-3-methoxy -13/3 -ethyl -18.19-dinorpregnal, 3.5 (10) -triene-20 -on (54 mg, 44%), melting point 170 to 171 °.

Example 59

dl-1la-acetoxy-17-hydroxy-3-methoxy-13/3-ethyl-18,19-dinorpregna-1,3,5 (10) -trien-20-one

dl-ll * -Acetoxy-3-methoxy-13/3-ethyl-18,19-dinorpregna-1,3,5 (10) -triene-17,20 / 9-diol (1.00 g) in dry, redistilled dimethyl sulfoxide (10 ml) and acetic anhydride (5 ml) was added for 24 hours at room temperature left to stand, then poured into sodium bicarbonate solution and extracted with ether. the Extracts were washed with water and brine, then dried over magnesium sulfate. Filtration and evaporation in vacuo gave an oil. This was recrystallized from ether / petroleum ether, and you received the = ketone (278 mg), melting point 206-209 °.

Example 60

dl-llftn-dihydroxy-n / S-ethyl-ie.W-dinor-3 (N-pyrrolidinyl) -pregna-3,5-dien-20-one

Example 57

dl-II / 9,17,20) J-Trihydroxy-3-methoxy-13/3-ethyl-18,19-dinorpregna-1,3,5 (10) -triene

Lithium aluminum hydride (3 g) was added to a stirred solution of dl-II / f-acetoxy-3-methoxy-130-ethyl-18,19-dinorpregna-1,3,5 (10) -triene-17,2O / 9- added diol (6.82 g) in tetrahydrofuran (100 ml) and then left the mixture at 25 ° for 16 hours. Methanol-ether, water and then dilute hydrochloric acid were added, the upper layer separated and combined with an ethereal extract of the lower aqueous phase, dried (MgSO ₄ ) and evaporated to a solid residue. This was then recrystallized from methanol, and the title compound (4.75 g, 78%), melting point 219 ° to 221 °, was obtained. The analytical sample had a melting point of 218 to 220 ° (from acetone-hexane). UV: 278 (1912), 287 (1801).

Analysis for C _M H _M O ₄ :

Calculated ... C 73.30, H 8.95%;
found .... C 72.90, H 8.85%.

Pyrrolidine (0.5 ml) was added to a solution of dl-II / S.n-dihydroxy-D / I-ethyl-lS.W-dinorpregn ^ -en-3,20-dione (407 mg) in methanol (25 ml) and tetrahydrofuran (25 ml) were added and the mixture under Nitrogen at 60 ° for 10 min. Stirred. The resulting pale yellow solution was cooled and in vacuo concentrated to an oil which crystallized on trituration with methanol. The crystalline product was filtered off, washed with ether and dried in vacuo. The solvated enamine was obtained

Title compound (431 mg; 92%), melting point 216-217 ° (dec.); UV: 278 (19,900).

Analysis for C ₂₅ H ₃₇ NO ₃ :

Calculated ... C 72.35, H 958%;
found .... C 72.31, H 9.61%.

Example 61

dl-N (21-bromo-110,17-dihydroxy-13/3-ethyl-18,19-dinor-20-oxopregn-4-en-3-ylidene) -pyrrolidi- nium bromide

The enamine (411 mg) from the previous example was dissolved in ethanolic hydrochloric acid (20 ml) ⁶ S with stirring. A freshly prepared solution of bromine (0.11 ml) in ethanol (4 ml) was added to this solution in the course of 30 minutes at 25 °. The resulting mixture was stirred for an additional 10 min. And the

so formed precipitate is filtered off and washed with ether. In this way, the desired one was obtained Pyrrolidinium bromide of the title compound (395 mg, 62.5%), melting point 260 °; UV: 279.3 (23,800). IR: 3300; 1715; 1615.

Example 62

dl-21-bromo-II / ?, 17-dihydroxy-13 ^ -ethyl-18,19-dinorpregn-4-en-3,20-dione

Saturated aqueous sodium bicarbonate (2 ml) was added to a solution of the pyrrolidinium bromide obtained above (244 mg) in ethanol (125 ml) was added and the mixture was stirred at 25 ° for 10 min. The Ethanol was then evaporated off in vacuo, water was added and the resulting precipitate was filtered off, washed with water and dried in vacuo. The desired title bromoketone compound was obtained (185 mg), mp 236 ° (dec.); UV: 242.6 (13050); IR: 3340, 1720, 1640, 1610.

Example 63

dl-21-acetoxy-II / J, 17-dihydroxy-13/3-ethyl-18,19-dinorpregn-4-en-3,20-dione

The bromo ketone (169 mg) from the previous example was dissolved in acetone (30 ml) and taken under Heated to reflux with potassium acetate for 4 hours. The mixture was evaporated in vacuo with water and treated methylene chloride, the organic layer separated and evaporated to a brown oil. This slowly crystallized and was recrystallized from acetone / petroleum ether; you got what you wanted 21-acetate (55 mg / melting point 225 to 228 °. UV: 242.5 (15 770). IR: 1747, 1738, 1720 1650, 1610.

Example 64

dl-21-Acetoxy-II ^, 17-dihydroxy-13 ^ -ethyl-18,19-dinorpregn-4-ene-3,20-dione

A solution of iodine (380 mg) in methanol (1 ml) and tetrahydrofuran (\ ml) was added to a stirred suspension of calcium oxide (350 mg) in a solution of dl-II & n-dihydroxy-IS / S-ethyl-IS.W -dinorpregn-4-en-3,20-dione (263 mg) in methanol (15 ml) and tetrahydrofuran (15 ml) were added. 50% aqueous calcium chloride (0.05 ml) was then added, followed by a further 280 mg of calcium oxide ^{after 1 1/2 hours.} After an additional 2V ₄ hrs. The pale yellow mixture was filtered and the precipitate washed with methylene chloride. The filtrate and wash liquors were combined and evaporated in vacuo to a light brown oil. This was dissolved in a mixture of acetone (65 ml), dimethylformamide (5 ml) and acetic acid (1 ml) and the solution stirred under reflux with potassium acetate for 18 hours.

The mixture was then cooled, extracted with methylene chloride and the extracts washed, dried and evaporated in vacuo. The residue so obtained was dissolved in methanol (10 ml) and heated under reflux for 1 hour with a solution of sodium metabisulfite (150 mg) in water (5 ml). The crude product was again isolated by extraction with methylene chloride, washed and dried and concentrated to a white crystalline residue (255 mg). This was then at a Florisil column eluted with solvent mixtures of ethyl acetate / acetone. The title compound (6.5 mg) was eluted in this way with 60% ethyl acetate / acetone, then obtained by recrystallization from acetone / petroleum ether, melting point 220 bis

Scheme 1 (first part)

MeO

Et

AcO \ OH

Ex 2

Scheme 1 (two part)

54

HO

MeO

OH

Claims (3)

Patent claims: 1. Process for the preparation of 13 / i-alkyl-S.ll.n ^ O ^ l-pentaoxylated-ISJii-dinorpregnenes the general formula —X wherein R ^{1 is} an n-alkyl group with 1 to 3 carbon atoms, X is a /? - [(2'-hydroxy- or protected hydroxy-) - l'-hydroxy-, protected hydroxy-, oxo- or protected oxo -) - ethyl] - «- (hydroxy or protected hydroxy) - methylene group, W is a λ- or / S-hydroxy or protected -hydroxy group or an oxo or protected oxo group, Y is a hydroxy group or a protected hydroxy group and the Ring A is aromatic or, if Y is an ether group, ring A contains the 2,5 (10) -diene system, or Y represents an oxo group and rings A and B have a double bond in the 4 (5) or 5 (10) position, or Y is a protected oxo group and rings A and B have a double bond in the 4 (5), 5 (10) or 5 (6) position, with or without a second double bond in the 2 (3) - or 3 (4) position, characterized in that one according to methods known per se (a) a 13 /? - alkyl-3-hydroxy- or protected -hydroxy-17f-ethylgona-1,3,5 (10), 9 (II) -tetraen-17f-ol in the 11 control to a 13 /? - alkyl-17 £ -äthylgona-1,3-5 (10) -triene-l 1.17f-diol hydroborated, (b) the 11-hydroxy function produced by des 13 / S-AIkyl-17 £ -äthyIgona-l, 3,5 (10) -trien-l, 17 £ -diols by converting to 11-oxo group, 11-protected, by a known method Protects an oxo group or an 11-protected hydroxyl group, (c) the 17-hydroxy function of the 11-oxo, protected -Oxo- or protected hydroxy-13 /? - alkyl-17 £ -äthylgona-1,3,5 (10) -trien-17f-ols under Formation of a corresponding 17-ethylidene compound dehydrated and optionally the protective group from the 11-oxo or H-hydroxy group removed, (d) 3-alkoxy-1,3,5 (10) -triene reduced to form a 3-alkoxy-2,5 (10) -diene according to Birch, (e) the product obtained from the Birch reduction to form a 5 (10) -en-3-one or 4-en-3-one hydrolyzed, (f) the 17-ethylidene group in 17-, 20- and 21 digits to form a 17,20,21-trioxygenated Oxidized derivative, steps (a) to (c) in the order given above and steps (d) to (f), of which (d) and (e) are optional steps to be carried out, in in any suitable order, with steps (d) and (e), if desired, be carried out between the various oxidation stages in stage (f) and if desired, one or more of the subsequent reaction steps are carried out in any suitable step carries out according to methods also known per se: (I) Oxidation of an 11-hydroxy group to one 11-oxo group, (Ii) reduction of an 11-oxo group to a 1 Iß- hydroxy group, (III) Coalign or convert a 3-oxo lip into an enol ether or enol ester group, (IV) converting an 11-hydroxy or 11-oxo group into an esterified 11-hydroxy or a ketalized 11-oxo group, (V) converting a 17- or 21-hydroxy group into an esterified hydroxy group, (VI) converting a 20-oxo group into a ketalized 20-oxo group, or (VII) Isomerization with an acid or a Base of a 5 (10) -en-3-one to a 4-en-3-one, or (VIII) Forming a 3-alkoxy group from a 3-hydroxy group or from a 3-protected hydroxy group other than a 3-alkoxy group. 2. Process for the preparation of a 13-alkylll-oxylated-18,19-dinorpregnan the general formula where R ^{1 is} an n-alkyl group having 1 to 3 carbon atoms, R ^{2 is} a hydroxy or protected hydroxy group and R ^{3 is} an ethyl group, or the radicals R ² and R ^s together form an ethylidene group, W is an oxo or protected oxo or a <x- or / i-hydroxy or protected hydroxy group and Y is a hydroxy or protected hydroxy group, in which case the ring A is aromatic or an etherified hydroxy group and the ring A is a 2,5 (10) -diene System or Y is a protected oxo group with the simultaneous presence of a double bond in the 4-, 5 (6) or 5 (10) position, with or without a second double bond in the 2- or 3-position, or an oxo group is, in which the rings A and B have a double bond in the 4-, 5 (10) or 5 (6) positions, characterized in that one according to known methods (a) a 13-alkyl-3-hydroxy- or protected -hydroxy -17f-ethylgona-1,3,5 (10), 9 (11) -tetraen-17f-ol hydroborated in the 11-position, (b) protects the 11-oxygen function formed and, if desired, (c) the 17-hydroxy function is dehydrated under Formation of an ethylidene group and in turn, (d) if desired, the 11- hydroxy group (after removal of the protecting group) epimerized to a 110-hydroxy group or a 11- hydroxy group oxidized to an 11-oxo group, the compound obtained by a Birch reduction and Subjected to hydrolysis, the 3-ketone obtained converted into a protected 3-ketone or the 11-hydroxy function again protects. 3. Process for the preparation of a 13-alkylll-oxylated-18,19-dinorpregnane the general formula R ¹ R ² bond in the 2- or 3-position, or is an oxo group, in which in this case the rings A and B have a double bond in the 4-, 5 (10) - or 5-hour periods, characterized in that that one obtainable according to claim Ie) by methods known per se 13 - alkyl - 3,11 - dioxylated - 18,15 - dinorpregn-17 (2O) -ene with further unsaturation in ring A. oxidized at the 17 and 20 positions.