DE1443466B - Process for the preparation of 2-ene-3ol ethers of 2-formyl-3-oxo-5alpha-steroids - Google Patents

Description

The invention relates to a process for the preparation of 2-en-3-ol ethers of 2-formyl-3-oxo-5a-steroids, which either have valuable biological properties themselves or as intermediates for the production of compounds with valuable biological properties are suitable. Some of the 2-formyl derivatives of the general formula II given below show remarkable claudogenic Properties (V. P e t r o w, J. Pharm. Pharmacol, 12, 1960, p. 704), which these compounds e.g. give importance to the field of veterinary medicine. For the further processing of the process products of the general formula II, their 2-formyl group can be used converted to a methyl group or with aromatic amines or with other carbonyl reagents be condensed. The 2-formyl derivatives obtained according to the process of the general Formula II can also be used with hydrazine or semicarbazide to give pyrazole derivatives or with hydroxylamine Oxazole derivatives condensed, d. H. processed into compounds with valuable anabolic properties (see Clinton, Manson, Stonner, Beyler, Potts and Arnold, J. Amer. Chem. Soc, 81, 1959, p. 1513; Clinton, Manson, Stonner, Christianson, Beyler, Potts and Arnold, J. Org. Chem., 26, 1961, P. 279).

Furthermore, the 2-formyl derivatives of the general formula II obtained according to the process can be converted into 2-hydroxymethyl derivatives be reduced.

The process according to the invention for the preparation of 2-en-3-ol ethers of 2-formyl-3-oxo-5a-steroids of the general formula II

b) a 3,3-dialkoxy-5a-steroid of the general formula III ■

CH,

(III)

in which R _{1 has} the meaning given above, or a corresponding 3,3-alkylenedioxy derivative is treated with at least 2 molar equivalents of the so-called Vilsmeier reagent by known methods

where R is an O-alkyl, O-hydroxyalkyl, O-cycloalkyl or O-aralkyl radical and R _{1 is} hydrogen or a methyl radical, consists in that one

a) a corresponding 2-en-3-ol ether of a 3-oxo-5a-steroid of the general formula I.

and that the complex formed according to a) or b) is then hydrolyzed in a manner known per se.

The reaction of the starting 2-en-3-olether with the Vilsmeier reagent is preferably carried out under carried out anhydrous conditions at or below room temperature and the resulting Complex hydrolyzed using aqueous-methanolic sodium acetate solution.

The Vilsmeier reagent (see e.g. Houben-We yl, Methods of Organic Chemistry, 4th edition, 1954, Vol. 7 (1), p. 29 ff.) Is known to introduce the aldehyde group into aromatic, quasi-aromatic and certain heterocyclic ring systems are used. Its application is in the steroid field not yet known. Its application according to the invention to the 2-en-3-older derivatives of 3-oxo-5a-steroids, to 3,3-dialkoxy-5a-steroids and 3,3-alkylenedioxy-5a-steroids lead to an important, highly specific and surprising development the technology, since the corresponding 2-en-3-olacetate (II) of 3-oxosteroids, in particular of 3-oxo-5a-ste-

roids, under the conditions of the process according to the invention, do not provide any 2-formyl derivatives.

Furthermore, it was surprisingly found that the starting compounds used against acidic reagents unstable 2-en-3-ol ethers, 3,3-dialkoxy-5a-steroids and 3,3-alkylenedioxysteroids are not split under the conditions of the process according to the invention.

The starting material for procedure a) according to the invention form the 2-en-3-ol ethers of 3-oxo-5a-steroids which are saturated in ring A and which contain a structure of the general formula I. These 2-en-3-ol ethers can be obtained by methods known per se, or they can, as described below, can be prepared and used in situ. So can the 2-en-3-olether under others are produced by methods such. B.

wherein R and R _{1 have} the meaning given above, reacted with the so-called Vilsmeier reagent by known methods or that one

a) Conversion of 3-oxo-5a-steroids saturated in ring A. in 3,3-dialkoxy derivatives of the general formula III and subsequent removal of AlkOH by pyrolysis or other methods known per se, the 2-en-3-ol ethers of the general formula I obtained

will;

b) in the case of the 2-en-3-ol ethers of 3-oxoandrostane, -19-norandrostans, -5a-pregnans, -

Gnans, -cholestans, -spirostans, -ergostans, -stigmastans and derivatives thereof and analogous compounds can obtain the required 2-en-3-ol ethers of the general formula I from the corresponding 3-oxo-zl ⁴ -steroids by converting them into the 3, 5-dien-3-olether of partial formula V

in which R has the meaning given above, and the catalytic hydrogenation thereof is obtained.

The term Vilsmeier reagent is generally understood to mean a reactant which is formed from a formylated secondary amine and an acid halide from the group of acid halides which are readily subject to nucleophilic replacement of a halogen ion on treatment with the N-formyl derivative of a secondary amine (see Sect. Bosshard * and Zollinger, HeIv. Chim. Acta, 1959, Vol. 42, .- p. 1659).

Various formamides, such as dimethylformamide, methylethylformamide, diethylformamide, methylphenylformamide, Ethylphenylformamide, formylpiperidine and formylmorpholine can be used. Dimethylformamide is particularly preferred as the formamide.

In addition to phosphorus oxychloride and phosgene, other acidic reagents such as phosphorus oxybromide can also be used and phosphorus pentachloride can be used. Thionyl chloride, oxalyl chloride and the like Acid halides can also be used. Phosgene is the preferred reagent.

Preferred method of manufacture
the 2-Formy Ideriva te

In the process according to the treatment of 3,3-dialkoxy derivatives of the general formula III with the Vilsmeier reagent, the corresponding 2-en-3-ol ethers of the general formula I are obtained first. These do not need to be isolated, but can be done in situ with a further amount of the Vilsmeier reagent are formylated, the desired 2-formyl derivatives of the general formula II arise.

In the process according to the treatment of a corresponding 3,3-alkylenedioxy derivative with the Vilsmeier reagent is first ier corresponding O-hydroxyalkyl-2-en-3-olether of the general formula I, wherein R is an O-hydroxyalkyl radical. This does not need to be isolated, but can be done in situ with a further amount of Vilsmeier's reagent are formylated to a 2-formyl derivative of the general formula II, in which R is an O-hydroxyalkyl radical means to receive.

Ketal derivatives of the formula III or corresponding cyclic alkylene ketals are used as starting materials All preferred, since they are generally more easily accessible than the corresponding 2-en-3-ol ethers of the general formula I. When using such ketal derivatives as starting material, it is necessary use at least 2 molar equivalents of Vilsmeier's reagent. If 2-en-3-olether of the general Formula I are used as starting materials, it is generally necessary to employ at least 1 molar equivalent of the Vilsmeier reagent.

The following reaction conditions are used to convert the 2-en-3-ol ethers of the general Formula I is preferably used in the desired 2-formyl derivatives. Are ketal derivatives of the general Formula III or corresponding alkylene ketals are used, the amount of phosgene is at least 2 molar equivalents increased. .

Phosgene (generally about 1 mole) is either used directly or dissolved in an organic solvent free of water and hydroxyl groups, e.g. B. dioxane or preferably a halogenated hydrocarbon, such as methyleride dichloride, chloroform, carbon tetrachloride or ethylene dichloride, added at ⁰ ° C. to a solution of dimethylformamide, preferably in one of the above-mentioned chlorinated hydrocarbons or in dioxane, the Vilsmeier reagent being formed . In order to obtain a reagent free from excess phosgene it must be ensured that no less than an equivalent amount of dimethylformamide is present and that the reagent is prepared under essentially anhydrous conditions.

The starting steroid ether is either in solution, preferably in one of the above halogenated hydrocarbons or in dioxane, or in a finely powdered state at 0 ° C Vilsmeier reagent added. The mixture is preferably stirred, with for exclusion of moisture is taken care of; the reaction is allowed to proceed spontaneously, the solution turning dark and the temperature of the mixture increases. Generally when working with small batches of material external cooling is not necessary; However, such cooling can be useful, if the implementation is carried out on a larger scale. Generally the reaction is after Completed 1 to 3 hours. The mixture is then used to decompose the complex in aqueous-methanolic Poured sodium acetate solution and isolated the product from the organic solvent layer. The 2-formylation reaction is applicable to enol derivatives of the general formula I, which additionally may contain further substituents as indicated below.

Hydroxyl groups

The Vilsmeier reagent is known to formylate free hydroxyl groups or through halogen replaced (see H ο u b e η — We y 1, op. cit.). It is therefore advantageous to protect hydroxyl groups beforehand by acylation and subsequently, if desired regenerate by hydrolysis or hydrogenolysis.

This is particularly useful in the case of 17a-substituted 17 / f-hydroxy derivatives.

Hydroxyl groups in positions 1, 2 and 4 interfere with the Vilsmeier reaction. Hydroxyl groups and functional modifications thereof, e.g. in positions 5, 6, 11, 12, 15, 16 (including 16-hydroxymethyl), 17, 18, 20 and 21 (including the condensation products of 16a, 17a-glycols with Carbonyl components), but generally allow the desired formylation on the carbon atom 2. Thiol groups in position 16 remain unaffected. . .Γ · '

Carbonyl groups

Carboxyl groups, e.g. in positions 11, 12, 16, 17, 18 and 20 'normally interfere with the formylation reactions not.

The process according to the invention is then explained in more detail by means of examples. For the Production of the starting compounds used according to the process is within the scope of the present Invention not seeking protection.

Carbalkoxy groups

Carbalkoxy groups in positions 13, 16 and 17 or in the side chain do not interfere with the formylation reactions. Cyano groups in positions 13, 16 and 17 also mostly allow normal formylation in the 2-position.

: Alkyl groups

Alkyl groups which differ from those in 2-position, in particular alkyl groups in position 4, 5, 6, 11, 16, 17 and 21, up to 6 carbon atoms ^r, the process of the invention do not interfere.

Alkenyl groups

example 1

Preparation of 17a-acetoxy-2-formyl-3-methoxy-5 a-pregn-2-en-20-one

CO · CH ₃

-OAc

20th

Vinyl and allyl groups in the 17-position interfere with this Method according to the invention does not.

Methylene and ethylidene groups in positions 6, 11, 16 (17), 16 and 17 interfere with the invention Procedure not.

Lactone, ether and spiroketal residues

Spirolactonreste as - O · CO · CH ₂ ■ CH ₂ -, which are connected to the C atom _17; Ether groups 30; in the 16-position and ether bridges in the 18, 20-position, spiroketal residues such as are present in Diosgenon, do not interfere with the process according to the invention.

Halogen groups

Chlorine, bromine or fluorine substituents in rings C and D or in the side chain interfere with this method according to the invention not.

Unsaturated bonds ^4C

Unsaturated bonds in position 9 (11), 11, 14, 16 and 17 (20) do not interfere with the method according to the invention.

45 ketol groups

Ketol groups in the 16.17, 17.20 and 20.21 positions are preferably acylated with the Vilsmeier reagent before the reaction according to the invention.

Corticoid side chains

The corticoid side chain can be acylated in the 21-position by reaction with formaldehyde with the formation of the bismethylenedioxy derivative, by the formation of the 17,21-cyclocarbonate or -acetonide or protected by other methods known per se and, if desired, subsequently regenerated will.

Epoxies ^

Corresponding lo / S-methyl-loajna-epoxypregnän-20-one derivatives can be converted into the corresponding 2-FormyIderivate of 17u-Hydroxy-16-methylenpregnan-20-one in one operation using about two mole fractions of Vilsmeier's reagent. 16a, 17a-epoxypregnan-20-one residues are in 16 ^ -halogen-na-hydroxypregnan-20-one structures converted.

A solution of 5.5 g of ny 5a-pregnan-20-one (m.p. = 190 to 191 ° C, as needles, [a] f = -4.0 [c = 0.97 in dioxane], prepared from the corresponding 3-ketone by treatment with a trace of oxalic acid-containing methanol) in 100 ml of dry ethylene dichloride containing a trace of pyridine is added at 0 ° C with stirring to a suspension of the complex, which consists of 3.3 ml of dimethylformamide and 1.9 g of phosgene in 30 ml of dry ethylene dichloride and allowing the mixture to warm to room temperature within 3 hours. A solution of 7.5 g of sodium acetate in 50 ml of methanol and 10 ml of water is added and stirring is continued for a further half an hour, after which the mixture is poured into water, washed and dried over sodium sulfate. The extract gives a gummy residue, which crystallizes from dichloromethane-methanol and produces Na-Acetoxy ^ -formyl ^ -methoxy-5a-pregn-2-en-20-one as a platelet with a melting point of 247 to 250 ⁰ C, [α] yields f = + 79.4 ° (c = 1.2 in chloroform), A £ ax ^{iOH =} 279 πΐμ (ε = 13 910).

Example 2

Preparation of 1 Ta-acetoxy ^ -formyl-S-methoxy-5a-pregn-2-en-20-one

17a - acetoxy - 3 - methoxy - 5a - pregn - 2 - en - 20 - one (m.p. = 182 to 184 ° C, [a] S '· ⁵ = + 39.5 ° [c = 0.7 in dioxane ]), which has been obtained either by pyrolysis of 17a-acetoxy-3,3-dimethoxy-5a-pregnan-20-one or by catalytic hydrogenation of na-acetoxy-S-methoxypregna-3,5-dien-20-one , is treated according to the procedure of Example 1 using half the amount of phosgene, 17a -acetoxy - 2 - formy 1 - 3 - methoxy - 5a - pregn - 2 - en-20-one with a melting point of 248 to 250 ° C obtained, which is identical to the compound obtained according to Example 1 in all respects.

Example 3

Preparation of 17 (3-acetoxy-2-formyl-3-methoxy-17a-methyl-5a-androst-2-en

OAc

\ CH ₃

H ₃ C

OHC-f

A solution of 1 g of Na-Methyl-Sa-androstan-17/3-ol-3-one (Rusicka, Meister and Prelog, HeIv. Chim. Acta, 1947, 30, p. 867) and 1 g of selenium dioxide in 80 ml Methanol is heated under reflux for 1 hour, cooled and a solution of 1 g of potassium hydroxide in 30 ml of methanol is added. 500 ml of water are added, whereupon the reaction product is filtered off and recrystallized from aqueous methanol; is obtained 3,3-dimethoxy-17a-methyl-5o-androstan-17 /? - ol in platelets with the F. 154-157 ⁰ C, ν ^ i ⁰ '= 1180, 1145, 1100 and 1040 cm' ^1.

A solution of 3 g of the abovementioned compound in 30 ml of acetic anhydride and 30 ml of pyridine is refluxed for 3 hours and poured into 250 ml of water. The reaction product is extracted with benzene, the extract is dried over sodium sulfate and filtered through a short aluminum oxide column, whereupon the solvent is evaporated off. Recrystallization of the residue from aqueous methanol (containing a trace of pyridine) is obtained which serves as the starting compound 17/3-acetoxy-3,3-dimethoxy-17a-methyl-5a-androstan in platelets with the F. 114 to 116 ⁰ C. , [α] 2 = + 7 ° (c = 0.62 in chloroform).

1 g of the above-mentioned compound is added with stirring to an ice-cold suspension of the Vilsmeier reagent (which is obtained by adding 7 ml of a 10% [w / v] solution of phosgene in ethylene dichloride to a solution of 1.2 ml of dimethylformamide in 10 ml of ethylene dichloride has been prepared), and the mixture is stirred at room temperature for 1 hour. The mixture is hydrolyzed with aqueous methanolic sodium acetate and the reaction product is isolated with ether. Recrystallization of the product from aqueous methanol gives 17 /} - acetoxy-2-formyl-3-methoxy-l 7a-methyl-5u-androst-2-en as needles with a melting point of 182 to 1-83 ° C, [ ü] j <= '+ 95 ° (c = 0.82 in chloroform), v ^ f = 1730, 1650 and 1610 cm-'.

Example 4

Preparation of 21-acetoxy-2-formyl-17α-hydroxy-3-methoxy-5a-pregn-2-en-ll, 20-dione
CH, OAc

-OH

OHC
CH, O

A suspension of 10.5 g of 21-acetoxy-3,3-dimethoxy-17a-hydroxy-5a-pregnan-II, 20-dione (Evans, Green, Hunt, Long, Mooney and Phillipp, Journ. Chem. Soc, 1958 , P. 1529) in 75ml dry ethylene dichloride is added with stirring to a cooled suspension of a complex prepared from 5 g phosgene and 5 g dimethylformamide in 75 ml dry ethylene dichloride, whereupon the mixture is allowed to warm to room temperature within 4 hours. A solution of 10 g of sodium acetate in 75 ml of methanol is added and stirring is continued for a further half an hour. The mixture is poured into water and the steroid extracted with ether. After the extract, washed with water and dried, has been evaporated off, a residue remains which is recrystallized from dichloromethane-methanol; 21-acetoxy-2-formyl-17α-hydroxy-3-methoxy-5a-pregn-2-en-ll, 20-dione is obtained as a platelet with a melting point of 263 to 265 ° C, [α]? = + 151 ° (c = 1.0 in pyridine), λ% £ ' ^ΟΗ = 278.5 ΐημ {ε = 13 790).

Example5

Preparation of 17jS-acetoxy-2-formyl-3-methoxy-19-nor-5a-androst-2-en

A solution of 5 g of H / S-hydroxy - ^ - nor-Sa-androstan-3-one (Bowers, Ringold and Denot, J. Amer. Chem. Soc, 1958, 80, p. 6115) in 50 ml of acetic anhydride and 50 ml of pyridine is heated on a steam bath for 1 hour. The mixture is poured into 1 liter of water and the precipitated solid is filtered off and washed with water. By recrystallizing the product from aqueous methanol, 17 / J-acetoxy-19-nor-5a-androstan-3-one is obtained as prisms with a temperature of 98 to 100 ^° C.

A solution of 4.2 g of the abovementioned compound and 500 mg of oxalic acid in 100 ml of methanol is refluxed for 2 hours, cooled and mixed with 5 ml of pyridine. The mixture is poured into 500 ml of water and the reaction product is isolated with ether. By recrystallizing the product from aqueous methanol, which contains a trace of pyridine, the starting compound 17β-acetoxy-3,3-dimethoxy-19-nor-5'-androstane is obtained as prisms with a temperature of 111 to 113 ° C, [«] 'J = + 14.8 ° (c = 1.01 in chloroform),

N ujol

=. 1730 cm

-1

300 mg of the abovementioned compound are converted into an ice-cold suspension with stirring of the Vilsmeier reagent (prepared by adding

009 528/289

of 5.5 ml of a 10% solution of phosgene in ethylene dichloride to a solution of 1 ml of dimethylformamide in 3 ml of ethylene dichloride), and the mixture is stirred for 2 hours at room temperature. The mixture is hydrolyzed with aqueous methanolic sodium acetate and the reaction product is isolated with ether. Recrystallization of the reaction product from aqueous methanol gives n / S-Acetoxy ^ -formyl-S-methoxy-1Q-nor-5/3-androst-2-en as a platelet, mp = 188 to 190 ° C, [a] S> = + 148 ° (c = 1.03 in chloroform), νS ⁰¹ = 1730, 1650 and 1610 cm- ¹ .

Example 6

Preparation of 21-acetoxy-2-formyl-17a-hydroxy-3-methoxy-5a-pregn-2-en-20-one

CH ₂ OAc

: OH

OHC

CH ₃ O

CO

A solution of 5 g of 21-acetoxy-17a-hydroxy-5a-pregna-3,20-dione (Rosenkranz and P a t a k i, U.S. Patent 2,596,562) and 200 mg of oxalic acid in 100 ml of methanol is refluxed for 3 hours. The mixture is cooled, treated with pyridine and poured into 1 l of water, whereupon the reaction product is isolated with ether. Recrystallization gives the starting compound 21-acetoxy-17a-hydroxy-3,3-dimethoxy-5a-pregnan-20-one.

1 g of the above compound is added to a ice-cooled suspension of the Vilsmeier reagent (prepared by addition of 7 ml of a 10 ° / _o solution of phosgene in ethylene dichloride to a solution of 1.2 ml of dimethylformamide in 10 ml of ethylene dichloride), and the mixture is stirred at room temperature for 1 hour. The mixture is hydrolyzed with aqueous methanolic sodium acetate and the reaction product is isolated with ether. Recrystallization of the reaction product gives 21-acetoxy-2-formyl-17u-hydroxy - 3 - methoxy - 5a - pregn - 2 - en - 20 - one, / £ ^: "' ^OH = 279 ταμ (f = 13 200), v ^ J ° '= 1740, 1730, 1650 and 1610 cm " ¹ .

Example 7

CH ₉ OAc

5 °

Preparation of 21-acetoxy-2-formyl-17a-hydroxy-3-methoxy-l 6β-methyl-5a-pregn-2-en-l 1,20-dione

A solution of 5 g of 21-acetoxy-17a-hydroxy-16 /? - methyl-5a-pregna-3, l 1,20-trion (Nathansohn, Winters and Testa, Experientia, 1961,17, p.448) and 200 mg of oxalic acid in 100 ml of methanol is refluxed for 2 hours. The mixture is cooled, treated with 5 ml of pyridine and poured into 1 l of water. The reaction product will recrystallized with ether, serving as the starting compound 21-acetoxy-17a-hydroxy-3,3 - dimethoxy -16/3 - methyl - 5α - pregna -11.20 - dione receives.

3 g of the above compound are added with stirring to an ice-cold suspension of a Vilsmeier reagent (which has been prepared by adding 21 ml of a 10% solution of phosgene in ethylene dichloride to a solution of 3.6 g of dimethylformamide in 30 ml of ethylene dichloride ), and the mixture is stirred at room temperature for 2 hours. The mixture is hydrolyzed with aqueous methanolic sodium acetate and the reaction product is isolated with ether. Recrystallization of the product gives 21-acetoxy-2-formyl-17a-hydroxy-3-methoxy-16 /? - methyl-5a-pregn-2-en-ll, 20-dione, / &" ^sOH = 279πΐμ ( _f = 13 500), i> lf '= 1740, 1730, 1705, 1650 and 1610cm- ¹ .

30th

Example 8

Preparation of 2-formyl-17a-hydroxy-3-methoxy-16a-methyl-5a-pregn-2-en-l 1,20-dione

CH ₃

CO

O:

OHC
CH, O

A solution of 2.5 g of na-hydroxy-loa-methyl-5a-pregna-3,11,20-trione (Heusler, Kebole, Meystre, Ueberwasser, Wieland, Anner and Wettstein, HeIv. Chim. Acta, 1959, 42 , P. 2043) and 100 mg of oxalic acid in 40 ml of methanol is heated under reflux for 4 hours, cooled and treated with 3 ml of pyridine. The mixture is poured into 500 ml of water and the reaction product is isolated with ether and recrystallized; the starting compound 17a-hydroxy-3,3-dimethoxy-16a-methyl-5a-pregn-11,20-dione, r ^ f ¹ = 1730, 1705 cm " ^{1, is obtained} .

A solution of 500 mg of the above dimethoxy compound in 5 mL of ethylene dichloride is added with stirring to an ice-cooled suspension of the Vilsmeier reagent (prepared by adding 3.5 ml of a 10% solution of phosgene in ^e n ethylene chloride to a solution of 0 , 6 ml of dimethylformamide in 5 ml of ethylene dichloride), and the mixture is stirred at room temperature for 1 hour. The mixture is washed with aqueous-methanolic sodium

acetate solution hydrolyzed and the reaction product isolated with ether. Recrystallization of the reaction product gives 2-formyl-17a-hydroxy-3-methoxy- 6a- methyl-5α-pregn-2-ene -11.20-dione, / ^ ⁵ ° ^H = 278.5 πΐμ ( _f = 13 650), ν ^ f = 1730, 1705, 1650, 1610 cm- ¹ .

Example 9

Preparation of 21-acetoxy-2-formyl-17α-hydroxy-3-methoxy-l 6a-methyl-5a-pregna-2.9 (l 1) -dien-20-one

CH,

A solution of 3.7 g of 21-acetoxy-17a-hydroxy-16a - methyl - 5 a - pregn - 9 (11) - en - 3,20 - dione (Ehrmann, Heusler, Meystre, Wieland and Wettstein, HeIv. Chim. Acta, 1959, 42, p. 2548) and 100 mg of oxalic acid in 50 ml of methanol is refluxed for 2.5 hours. The mixture is cooled, treated with 5 ml of pyridine and poured into 500 ml of water. The reaction product is isolated with ether and recrystallized, the 21-acetoxy-17α-hydroxy-3,3-dimethoxy-16α-methyl-5a-pregn-9 (II) -en-20-one serving as the starting compound receives.

1.5 g of the above-mentioned compound are added to an ice-cold suspension of the Vilsmeier reagent (which has been prepared by adding 10.5 ml of a 10% solution of phosgene in ethylene dichloride to a solution of 1.8 ml of dimethylformamide in 10 ml of ethylene dichloride was) given with stirring, and the mixture is stirred at room temperature for 1.5 hours. The mixture is hydrolyzed with aqueous-methanolic sodium acetate solution and the reaction product is isolated with ether. The reaction product is recrystallized, 21-acetoxy-2-formyl-17α-hydroxy-3-methoxy-16a-methyl-5a-pregna-2,9 (l l) -dien-20-one, / ££ ⁵ ° ^H = 279πΐμ (ε = 13 800), »SS" = 1735, 1725, 1650, 1610 cm " ¹ is obtained.

Example 10

Preparation of 17 ^ -acetoxy-2-formyl-3-methoxy- ' lo / S-methyl-Sa-androst ^ -en

OAc

H, C

I,

A solution of 10 g of 17/3-acetoxy-16 (S-methyl-5a-androstan-3-one (Ruggieri, Ferrari and Gandolgi, Gazz. Chim. Ital., 1961, 91, p. 686) and 250 mg of oxalic acid in 150 ml of methanol is heated under reflux for 3 hours. The mixture is cooled, mixed with 5 ml of pyridine and poured into 1.2 l of water. The reaction product is isolated with ether and recrystallized -3,3-dimethoxy-16/3-methyl-5a-androstane, ν ™ $? ^] = 1735 cm " ¹ .

A solution of 5 g of the above compound in 50 ml of ethylene dichloride is under Stirring an ice-cold suspension of the Vilsmeier

(Which has been prepared by adding 35 ml of a 10 ° / _o solution of phosgene in ethylene dichloride to a solution of 6 ml dimethylformamide in 50 ml of ethylene dichloride) reagent was added and the mixture is stirred for 1 hour at room temperature. The mixture is hydrolyzed with aqueous-methanolic sodium acetate solution and the reaction product is isolated with ether. Recrystallization of the product gives 17/3-acetoxy-2-formyl-3-methoxy-1 6β- methyl-5α-androst-2-ene, λ üä "' ⁰ " = 279ΐημ (? = 13,900 _{), v Nujoi =} 1735, 1650, 1610 cm- '.

Example 11

Preparation of 17i? -Acetoxy-2-formyl-3-methoxy-17a-methy 1-19-nor-5a-androst-2-en

OHC

CH ₃ O

OAc

γ CH,

A solution of 5 g of nβ-hydroxy-na-methyl-19-nor-5a-androstan-3-one (Bowers, Ringold and Dorfman, J. Amer. Chem. Soc, 1957, 79, p. 4557) in 50 ml Acetic anhydride and 50 ml of pyridine are refluxed for 4 hours. The mixture is cooled, poured into water and the reaction product is isolated with ether. Recrystallization gives 17 ^ -acetoxy-17a-methyl-19-nor-5a-androstan-3-one, ν ^ = 1735, 1710 cm " ¹ .

A solution of 2.9 g of the abovementioned compound and 100 mg of oxalic acid in 50 ml of methanol is refluxed for 3 hours. The mixture is cooled, treated with 5 ml of pyridine and poured into 500 ml of water. The reaction product is isolated with ether and recrystallized, giving the starting compound 17/3 - acetoxy - 3,3 - dimethoxy -17a - methyl -19 - nor 5 «-androstane, ν S" = 1735 cm " ¹ .

Ig the above compound is stirred into an ice-cold suspension of the Vilsmeier reagent (obtained by adding 7 ml of a 10% phosgene solution to a solution of 1.2 ml

Dimethylformamide has been prepared in 5 ml of ethylene dichloride) was added, and the mixture is stirred at room temperature for 2 hours. The mixture is hydrolyzed with aqueous-methanolic sodium acetate solution and the reaction product is isolated with ether. Recrystallization of the reaction product gives 1 7 /? - acetoxy-2-formyl-3-methoxy-17a-methyl-19-nor-5 "-androst-2-ene, /. € _a ^ ^0H = 279.5 ηΐμ ( f = 12 900) ^{,, 'It 1} = 1V35, 1650, 1610 cm " ¹ .

EXAMPLE 12

Preparation of n / J-Acetoxy ^ -formyl-S-methoxy-6a, l 7a-dimethyl-5ct-andrqst-2-en

OAc

H ₁ C

20th

c CH,

OHC

30th

Example 13

Preparation of 17 ^ -acetoxy-2-formyl-3-methoxy-5a-androst-2-en

OAc

H,

35

A solution of 5.6 g of 6a, 17a-dimethyl-5a-androstane-17 ^ -ol-3-one (USA. Patent 2,936,312) in 50 ml of pyridine and 50 ml of acetic anhydride is refluxed for 4 hours. The mixture is cooled and poured into 1 l of water, whereupon the reaction product is isolated with ether. Recrystallization of the reaction product gives n / I-acetoxy-oa.na-dirnethyl-sa-androstan-3-one, "-Si ⁰¹ = 1735, 1715 cm" ¹ .

A solution of 4 g of the above-mentioned compound and 150 mg of oxalic acid in 60 ml of methanol is refluxed for 3 hours and then cooled, whereupon the mixture is treated with 4 ml of pyridine. The mixture is poured into 600 ml of water and the reaction product is isolated with ether. Recrystallization of the reaction product gives the starting compound n / J-acetoxy-SS-dimethoxy-öa.na-dimethyl-5a-androstane, ν ^ j ⁰ '= 1735 cm " ¹ .

1 g of the above compound, is added with stirring to an ice-cooled suspension of the Vilsmeier reagent (prepared by addition of 7 ml of a 10% strength solution of phosgene ^e n in ethylene dichloride to a solution of 1.2 ml of dimethylformamide in 10 ml of ethylene dichloride) given, and the mixture is stirred at room temperature for 1 hour. The mixture is hydrolyzed with aqueous-methanolic sodium acetate solution and the reaction product is isolated with ether. Recrystallization of the reaction product gives 17 / i-acetoxy-2-formyl-3-methoxy-6a, 17a-dimethyl-5 "-androst-2-ene, £ # ^0H = 279 πΐμ ( _f = 13,900), * £! * ". = 1735, 1650, 610 cm" ¹ . ■ ■ .. ■■ · .. ■

5cc-androstane, m.p. 143 to 144 ° C (prepared from the corresponding 3-ketone by treatment with methanol, which contains a trace of oxalic acid), are added with stirring to an ice-cold suspension of the Vilsmeier reagent (which is obtained by adding 70 ml of a 10% solution of phosgene in ethylene dichloride to a solution of 15 ml of dimethylformamide in 75 ml of ethylene dichloride). The mixture is stirred at room temperature for 70 minutes; it is hydrolyzed with aqueous-methanolic sodium acetate solution and the reaction product is isolated with ether. Recrystallization of the reaction product from methanol-methylene chloride gives 17 /? - acetoxy-2-formyl-3-methoxy-5a-androst-2-ene with a melting ^{point of} 210 to 214 ° C, λ ££ sOH = 279 ΐημ ( _ε = 13 800), v ^ = 1740, 1660, 1620 cm " ¹ .

The 2-formyl derivatives which have been prepared according to the preceding examples have claudogens Activity.

Claims (2)

Patent claims: 1. Process for the preparation of - 2-en-3-ol ethers of 2-formyl-3-oxo-5a-steroids of the general Formula II CH3 (Π) wherein R is an O-alkyl, O-hydroxyalkyl, O-cycloalkyl or O-aralkyl radical and R _{1 is} hydrogen or a methyl radical, characterized in that a) one. corresponding 2-en-3-olether of a 3-oxo-5a-steroid of the general formula I. CH ₃ (I) wherein R and R _{1 have} the meaning given above, reacted with the so-called Vilsmeier reagent by known methods or that one b) a 3,3-dialkoxy-5a-steroid of the general formula III AIkO
AIkO (III) in which R _{1 has} the meaning given above, or a corresponding 3,3-alkylenedioxy derivative is treated with at least 2 molar equivalents of the so-called Vilsnieier reagent by known methods and that the complex formed according to a) or b) is then used in a manner known per se hydrolyzed. 2. The method according to claim 1, characterized in that the implementation of the starting 2-en-3-olether with the Vilsmeier reagent under anhydrous conditions at or below room temperature and the thereby complex formed hydrolyzed by means of aqueous-methanolic sodium acetate solution. 009528/289