DE1212965B - Process for the preparation of A-Nor-B-homosteroids - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

Number:
File number:
Registration date:
Display day:

C 07c

German KL: 12 ο - 25/02

C29441IVb / 12o
March 22, 1963
March 24, 1966

The present invention relates to a process for the preparation of 3-oxo- and 3,6-dioxo-A-nor-B-homosteroids, starting from 3-oxo-4,5-oxido-steroids.

The compounds mentioned form a new class of biologically active steroids or Intermediate products for their representation. In particular, the 3,6-dioxo-A-nor-B-homo-androstanes have and -z ^ -androstene, which in 17 / J-position a have free or esterified hydroxyl groups, like the corresponding 3-oxo compounds, at very low androgenic activity has high anabolic efficacy. The 3,6-Dioxo-A-nor-B-homopregnane compounds, in particular those which have an oxo group in the 20- and optionally in the 11-position, in 17- and / or in 21- and conversion have hydroxyl groups are particularly as novel compounds with anti-inflammatory or anti-estrogenic and progestative effects of great interest.

The steroids known to date with A-nor-B-homo-structure, 6-oxo-A-nor-B-homo-cholestane and the 6-oxo-17β-hydroxy-5a- and -5 / i-A-nor-B-homo-androstane and their 17-benzoates were made by basic treatment of the corresponding 4a-Toxyloxy-5a-hydroxy compounds.

It has now been found that A-nor-B-homosteroids can be obtained in a novel and simpler way if a 3-oxo-4,5-oxidosteroid is used, optionally with temporary protection of groups which are not inert under the reaction conditions , irradiated with ultraviolet light in the presence of an organic solvent and, if desired, the 3,6-dioxo-A-nor-B-homo-steroid obtained in a manner known per se in its functional ketone derivatives derived from the enol form, in particular with acylie process for the production of
A-nor-B-homosteroids

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative:

Dr.-Ing. Dr. jur. F. Redies,

Dipl.-Chem. Dr. rer. nat. B. Redies,

Dr. rer. nat. D. Türk and Dipl.-Ing. Ch. Gille,

Patent Attorneys, Opladen, Rennbaumstr. 27

Named as inventor:

Dr. Oskar Jeger,

Dr. Kurt Schaffner, Zurich (Switzerland)

Claimed priority:

Switzerland of March 23, 1962 (3533),
dated August 17, 1962 (9844),
dated December 7, 1962 (14 422),
dated March 7, 1963 (2880)

Sending agents converted into the corresponding 6-enol acylates and / or converted into its metal salts, in particular copper complexes, or reacted with hydrazines and, if desired, obtained J ⁵ -3-oxo- acyloxy-A-nor-B-homosteroids catalytically hydrogenated or obtained A-nor-B-homosteroids with functionally modified hydroxyl and / or keto groups hydrolyzed.

The present method is e.g. B. illustrated by the following partial formula scheme:

RiO

R = H or CH ₃ Ri = H or acyl

609 539/432

The 3-Οχο-4α, 5α- and -4 / ?, 5jS-oxidosteroids used as starting materials, saturated in position 1 and 2, can be obtained from the corresponding ^^ - oxo compounds in a manner known per se, e.g. B. by treatment with alkaline hydrogen peroxide or peracids, or by hydrogenation of the A ¹ -3- oxo-4,5-oxido-steroids. The last-mentioned starting materials are new; surprisingly, they can be obtained directly from the ^! • ⁴ -3-oxo-steroid dienes by treatment with peracids, e.g. B. with organic peracids, such as lower aliphatic and aromatic peracids, e.g. B. with peracetic acid, benzoperic acid and phthalic monoperic acid, or by dehydration of the above 1,2-saturated 3-oxo-4,5-oxido-steroids, e.g. B. with selenium dioxide or dicyanodichloroquinone can be obtained.

The irradiation of the 3-oxo-4,5-oxido-steroids according to the procedure is in an organic solvent, e.g. B. in an aliphatic or cycloaliphatic Hydrocarbon, such as pentane, hexane, cyclohexane or methylcyclohexane, carried out. Particularly aliphatic and cyclic ethers, such as. B. diethyl ether and dioxane.

Artificial or strong natural light are suitable as the light source; preferably ultraviolet light, such as that produced by low-pressure and high-pressure mercury burners, or strong sunlight is used. The irradiation is preferably carried out at temperatures between 0 and + 8O ⁰ C.

In the 3,6-dioxo-A-nor-B-homosteroids obtained as reaction products, which are predominantly in enol form as ß-diketo compounds, can optionally present ester or protective groups, such as. B. ketals or Bismethylenedioxy groups, are cleaved hydrolytically. On the other hand, the process products in a manner known per se in their functional ketone derivatives which can be derived from the enol form as well be converted into metal salts. So you get z. By acylation, e.g. B. by treatment with carboxylic anhydrides, such as acetic anhydride or propionic anhydride, the corresponding enol esters and with etherifying agents such as B. alcohols or thioalcohols in the presence of acidic catalysts, enol ethers or thioenol ethers. By reacting the 3,6-dioxo-A-nor-B-homosteroids with hydrazines, cyclic hydrazones are formed, which are also regarded as pyrazole derivatives can. The corresponding copper complexes are formed by reaction with copper (II) salts.

^{The zl 5} -3-oxo-6-acyloxy-A-nor-B-homo-steroids prepared according to the process can be prepared by catalytic hydrogenation in a manner known per se, such as by hydrogenation z. B. in benzene or alcohol, with palladium carbon or palladium-barium carbonate catalyst, in the corresponding saturated, 6-unsub-. substituted 3 - oxo - A - nor -B - homo - steroids are converted.

The 3-Οχο-4α-5α- and -4 / ?, 5 ^ -oxidosteroids used as starting materials for the present process preferably belong to the series of Androstane, Pregnane, Cholane, Cholestane, Spirostane and Cardanolide as well as the corresponding 19-Nor series and can in addition to the mentioned groupings in one or more of the positions 6, 7, 8, 9, 11, 12, 14,15, 16, 17, 18, 19, 20 and 21 have further substituents, such as alkyl (ζ. B. methyl) groups and / or halogen atoms, free or functionally modified oxo groups and free, esterified or etherified hydroxyl groups. In addition, the starting materials Contain double bonds, in particular as mentioned above, between the carbon atoms 1 and 2. It is also possible to use mixtures of the two epoxides isomeric in the 4,5-position.

Particularly important starting materials are z. B. the following compounds: 3-oxo-4a, 5a-oxido and -4 / ?, 5/3-oxido-17-hydroxy-androstane and its esters, 3,17-dioxo-4a, 5ct-oxido and -4 /?, / S-oxido-androstane and its 17-ÄthylenketaI, 3-oxo-4a, 5a-oxido and -4 ^, 5 ^ -oxido-17a-alkyl-, -17a-alkenyl- and -17a -alkynyl - Π β - hydroxy - androstane and their esters, such as the 3 - oxo - 4α, 5α - oxido and -Aß, 5ß - oxido-17; S-hydroxy-17a-methyl-, -17a-ethyl- , -17a-vinyl-, -17a-äthinyl- and -17a-allyl-androstane, 3,20-dioxo-4a, 5a-oxido- and -4 / J, 5 /? - oxidopregnane, 3,20-dioxo- ■ 4a, 5a-oxido- and -4 / 9,5 ^ -oxido-17a-hydroxypregnane and their esters, 3,20-dioxo-4a, 5a-oxido- and -4 / 3,5 / 5-oxido-21 -hydroxy-pregnane and its esters, 3,20-dioxo-4α, 5α-oxido- and -4β, 5β- oxido-17a, 21-dihydroxy-pregnane, their esters and 17,20; 20,21-bis-methylenedioxy compounds , 3.20 - Dioxo - 4α, 5α - oxido and -4 / 3-5 / 9-OXIdO-II / ?, na ^ l-trihydroxy-pregnane, their esters and 17.20 520,21-bis-methylenedioxy compounds , as well as z. B. the lactone of «d ¹ -3-oxo-4,5-oxido-17 / S-hydroxy-17a - (/ 5-carboxyethyl) -androstens and the l-dehydro-4,5-oxidotestololactone, also the in Position 1 and 2 unsaturated derivatives of the above compounds. The 17- or 20-oxo compounds are preferably used in the form of their 17- or 20-monoketals.

Compounds of the formulas I and II CH ₂ -R _{9 are particularly valuable}

II

where Ri stands for 2 hydrogen atoms or an oxo group, R2 for 1 hydrogen atom or an a- or / ^ - lower alkyl group, R3 for 1 hydrogen atom, an a- or / ^ - lower alkyl radical or a free, esterified or etherified hydroxyl group, R4 for a Oxo group or a free, esterified or etherified ^ hydroxyl group and

1 hydrogen atom, a lower aliphatic hydrocarbon radical or a free or esterified jS-carboxyethyl group, R5 for an oxo group,

2 hydrogen atoms or 1 hydrogen atom and a free or esterified hydroxyl group, R ₆ and R7 for 1 hydrogen atom, a lower alkyl radical or a free, esterified or etherified hydroxyl group, Rs for a free or ketalized oxo group or 1 hydrogen atom and a free, etherified or esterified hydroxyl group and R9 stands for 1 hydrogen atom or a free, esterified or etherified hydroxyl group, their tautomeric forms, e.g. B. their 3- or 6-enols and their functional derivatives and their 1-dehydro derivatives.

The compounds of the formula I in which R _{4 is} a free esterified or etherified hydroxyl group and

I have a hydrogen atom, show a favorable anabolic-androgen ratio, those in which R ₄ contains a lower alkyl group also show this effect when administered orally. If R _{4 contains} an unsaturated hydrocarbon radical, in particular a vinyl, allyl, ethynyl or propynyl group, which is also halogenated, e.g. B. can be fluorinated, these compounds show gestagenic or ovulation-inhibiting effects. The compounds of the formula II, in which Rs stands for an oxo group and Rg for 1 hydrogen atom, show particularly good progestative properties, those which have a 17-acyloxy group with less than 4 carbon atoms can also be administered orally and those in which the 17- Acyloxy group contains more than 4 carbon atoms, show a protahierte effect after parenteral administration. 21- and where applicable

II -substituted compounds, especially those with a 11 / ^ - hydroxyl group, have an anti-inflammatory and the electrolyte balance regulating effect. The new A-Nor-B-homo-cholestane show anticholesterolemic activity.

In the above-mentioned esters, the acid residues are in particular those of aliphatic, cycloaliphatic, araliphatic, aromatic and heterocyclic carboxylic acids with 1 to 15 carbon atoms, z. B. formates, acetates, propionates, butyrates, trimethylacetates, capronates, valerianates, Oenanthate, Decanoate, Cyclopentylpropionate, Hexahydrobenzoate, Phenylpropionate, Benzoate, Furoate, Trifluoroacetate, ethyl or methyl carbonate.

The new pharmacologically active compounds can be used as drugs in the human and veterinary medicine, e.g. B. in the form of pharmaceutical preparations can be used. These contain the new compounds together with pharmaceutical organic or inorganic, solid or liquid carriers suitable for enteral, e.g. B. oral, parenteral or topical administration are suitable. For the formation of the same substances come into question that do not react with the new compounds, such as B. water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, Gum, polyalkylene glycols, petrolatum, cholesterol, and other known excipients.

The pharmaceutical preparations can be in solid form, e.g. B. as tablets, coated tablets or capsules, or in liquid or semi-liquid form as solutions, suspensions, emulsions, ointments or creams are present. If necessary, these pharmaceutical preparations are sterilized and / or contained Auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for modification osmotic pressure or buffer. You can also use other therapeutically valuable substances contain. They are produced in a known manner. They contain the active ingredient in a large amount from 0.1 to 200 mg per unit dose or from 0.03 to 50%, especially from 0.1 to 10% by weight.

The procedure is described in more detail in the following examples. The temperatures are in degrees Celsius specified. The UV absorption spectra are recorded in ethanol solution, and the specific Rotations are measured in chloroform solution in a tube 1 dm in length.

The UV irradiations are carried out under a nitrogen atmosphere in a quartz vessel, in which the light source is centrally located and cooled with water. Low-pressure burners serve as light sources NK 6/20 (monochromatic light with a wavelength of 254 πΐμ) and high-pressure burner Q 81 (both Quarzlampen GmbH. Hanau).

Unless described in more detail, the reaction mixture is worked up as follows: it is taken up in ether, washing the organic phase with water until neutral and evaporating the ether solution dried over anhydrous sodium sulphate in a rotary evaporator. For chromatography Unless otherwise stated, the amount of neutral aluminum oxide is 30 times the activity II used.

For the production of the starting materials, protection is not given in the context of the present invention desired.

example 1

a) 15 g of 1-dehydro-testosterone acetate are in a solution of benzoperic acid in 130 ml of chloroform (8.5 mg / ml) left in the dark at room temperature for 4 days. The reaction solution is then diluted with ether and successively with aqueous potassium iodide and sodium thiosulphate solution shaken. A partially crystalline crude product is obtained which is chromatographed on aluminum oxide will. Benzene-hexane (2: 1) mixture elutes 3.6 g of a crystalline fraction and benzene-ether (1: 1) mixture 7.5 g of unchanged starting material.

The first fraction is recrystallized four times from acetone-hexane and yields 2.15 g! -3-Οχο-4 / ?, 5ß-oxido-17j8-acetoxy-androsten with a constant temperature of 144 to 145 °; [<z] _D = + 250 ° (c = 1.02). UV spectrum: Imax = 232 πΐμ (log ε = 3.96). IR spectrum (CHCl ₈ ): ν = 1725, 1680, 1623, 1255 cm- ¹ .

^{130 mg / J 1} -3-oxo-4a, 5a-oxido-17 ^ -acetoxy-androsten with a constant temperature of 139 to 141 ° can be obtained from the mother liquor products by recrystallization (twice from acetone-hexane and eight times from ethanol). UV spectrum: ?. _max = 227.5 πΐμ (log ε = 4.02). IR spectrum (CHCl ₃ ): ν = 1722, 1677, 1612, 1256 cm- ¹ .

b) 200 mg ^ ¹ -3-Oxo-4 _J ö, i) / 9-oxido-17 | S-acetoxy-androstene are in the presence of 200 mg 5%

Palladium carbon hydrogenated in 10 ml of benzene. After the uptake of hydrogen (1 mol) has ceased, the solution is filtered through diatomaceous earth (known under the trade name Celite), evaporated in vacuo and the residue is recrystallized from acetone-hexane; 153 to 155 ° F. UV spectrum: final absorption at 210 ηΐμ (log ε = 3.36). IR spectrum (CHCl ₃ ): ν = 1725, 1260 cm- ¹ . [a] ₀ = + 131 ° (c = 1.85). The product is according to Misch-F. and IR spectrum identical to an authentic preparation of S-Oxo - ^. SjS-oxido-ITjS-acetoxy-andro - .. stan; 153 to 155 ° C, [α], = + 135 ° (c = 1.30).

c) 30 mg of zI ¹ -3-Oxo-4a, 5a-oxido-17 / S-acetoxy-androstene are mixed with 30 mg of 5% PaUadium carbon in 3.5 ml of benzene like the Α ^ -Οχο ^ β, δβ-οχίάο - Is 17 ^ -acetoxy-androsten in Example 1, b) hydrogenated. After crystallization from acetone-hexane, the resulting product melts constantly at 164 to 165 °. [a] ₀ = -68 ° (c = 0.64). UV spectrum: final absorption at 210 πΐμ (log ε = 3.49). IR spectrum (CHCl ₃ ): ν = 1715, 1268 cm ^-1 .

d) 2.0 g / l ¹ -3-Oxo-4 / S, 5j? -oxido-17 / S-acetoxy-androstene are dissolved in 200 ml of dioxane and irradiated with a low-pressure burner for 40 hours. The solution is then evaporated in vacuo. The crystalline residue shows no more starting material in the thin-layer chromatogram (mobile phase: benzene — methanol [19: I]). After redissolving three times from methylene chloride-methanol, 160 g of z ^^ o-dioxo-U / S-acetoxy-A-nor-B-homoandrosten with a constant temperature of 171 ° to 172 ° are obtained. FeCl ₃ -TeSt: positive, [a] _D = + 98 ° (c = 0.65). UV spectrum: λτηαχ = 239τημ (log ε = 3.96), 3.11 ηΐμ (log F = 3.87). IR spectrum: ν = 1730, 1670, 1618, 1260 cm- * (CHCl3); ν = 1730, 1658, 1609, 1567 (weak), 1256 cm " ¹ (Nujol).

e) 380 mg of ¹ -3-oxo-4a, 5a-oxido-17 / S-acetoxy-an- 'drosten, dissolved in 100 ml of dioxane, are irradiated with a low-pressure burner for 2 hours and the solution is then evaporated in vacuo. In the thin-layer chromatogram (mobile phase: benzene-methanol- ^: I]) of the residue there is no longer any starting material. Chromatography on silica gel with a benzene-ether (19: I) mixture gives 200 mg of crystals which, after being redissolved three times from methylene chloride-methanol, melt at 164 ° to 166 ° (130 mg). Sublimation in a high vacuum at 150 ° gives the pure zl ¹ -3, 6-dioxo-17 / S-acetoxy-A-nor-B-homoandrosten with a temperature of 171 to 172 °, which, according to a mixed sample, has a specific rotation ([ a] _D = + 93 ° [c = 0.74]) and IR spectrum is identical to the photoproduct described in Example 1, d).

Example 2

55

450 mg of 4 ¹ -3,6-dioxo-17 / S-acetoxy-A-nor-B-homoandrosten are hydrogenated in 50 ml of benzene in the presence of 450 mg of 5% strength potassium carbon. After the uptake of hydrogen has ceased (1 mol after 30 minutes), the solution is filtered through "Celite" and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel. Benzene-ether (9: 1) mixture elutes 360 mg of crystals, which are redissolved three times from methylene chloride-methanol and 310 mg of Sjo-Dioxo-n / I-acetoxy-A-nor-B-homoandrostane with a constant temperature of 154 bis Deliver 156 °. FeCl ₃ -TeSt: positive. [a] _D = + 47 ° (c = 0.72). UV spectrum: X _max = 291 ιημ (log ε = 3.96). IR spectrum (CHCl ₃ ): v = 1721, 1641, 1608, 1255 cm- ¹ .

Example 3

1.20 g of 3-oxo-4 / 9,5ß-oxido-17/3-acetoxy-androstane in 120 ml of dioxane are irradiated for 54 hours with a low-pressure burner, and the solution is then evaporated in vacuo. According to thin-layer chromatography (mobile phase: benzene — methanol [19: I]) the residue contains starting material and about 25% 3,6-dioxo-17 / S-acetoxy-A-nor-B-homo-androstane. FeCl ₃ -TeSt: positive. UV spectrum: Xmax = 293 πΐμ (log ε = 3.32). The two compounds are difficult to separate by chromatography on silica gel. With benzene only 35 mg of uniform crystals are eluted, which melt after redissolving from methylene chloride - methanol at 154 to 156 ° and after mixed sample, IR spectrum, UV spectrum {X _max = 291 πΐμ; log ε = 4.01) and specific rotation ([a] _D = + 44 °, c = 0.64) are identical to the photoproduct described in Example 2.

Example 4

450 mg of 3-oxo-4 / 5.5 / S-oxido-17 ^ -acetoxy-androstane in 100 ml of dioxane are irradiated with a high-pressure burner for 2 hours. The residue of the solution evaporated in vacuo contains, according to thin-layer chromatogram ( mobile phase : benzene-methanol [19: I]), UV spectrum {Xmax = 291 πΐμ; log ε = 3.61) and FeCl ₃ -TeSt (positive) about 45% 3,6-Dioxo-17 / S-acetoxy-A-nor-B-homo-androstane and no more starting material. Chromatography on silica gel with a benzene-ether (9: 1) mixture gives 200 mg crystals which, after redissolving three times from methylene chloride-methanol, melt at 154 to 156 ° (100 mg) and, according to the mixed sample and IR spectrum, with that in Example 2 described connection are identical.

Example 5

80 mg of 3-oxo-4a, 5a-oxido-17 ^ -acetoxy-androstane are irradiated in dioxane in an open quartz test tube with a low-pressure burner for 10 hours, and the solution is then evaporated in vacuo. According FeCl ₃ test (positive), thin-layer chromatography (eluent: benzene-methanol [19: C]), and UV spectrum {X _ma x = 293 ΐημ, log ε = 3.41) of the residue contains, inter alia, the starting material and about 28 % of the photo product described in Example 2. The mixture, which is difficult to separate, is chromatographed on silica gel, with benzene eluting about 4 mg of uniform crystals with a melting point of 154 ° to 156 °. According to Misch-F., IR ^: spectrum and UV spectrum (Imax = 291 ΐημ, log ε = 3.97) with 3,6-dioxo-17E-acetoxy-A-nor-B-homo-androstane identical.

Example 6

440 mg of zli-Sjo-Dipxo-nß-acetoxy-A-nor-B-homoandrosten are allowed to stand in 10 ml of acetic anhydride-pyridine (1: 1) mixture for 6 days at room temperature. The solution is then evaporated to dryness in vacuo and the crystalline residue in benzene-ether (9: 1) solution is filtered through silica gel. This resulted in 350 mg of ^^ - Οχο-β, Ώß-di acetoxy-A-nor-B-homo-androstadiene, which after redissolving three times from acetone-hexane at 120 to

121 ° melts. FeCl ₃ -TeSt: negative. |>] ₀ == + 103 ° (c = 0.91). UV spectrum: λη _αχ = 24% ΐημ (log f = 3.94). IR spectrum (CHCl ₃ ): ν = 1755, 1722, 1703, 1649, 1595, 1255, 1165 cm- ¹ .

Example 7

200 mg / l ^ jo-Dioxo-njS-acetoxy-A-nor-B-homoandrosten are hydrolyzed in 5 ml of saturated methanolic potassium carbonate solution for 24 hours at room temperature. Extraction with ether gives 150 mg /! ^, Δ-dioxo-nß-hydroxy-A-nor-B-homo-androstene, which melts constantly at 156 to 159 ° after being redissolved three times from methanol. IR spectrum (Nujol): ν = 3560, 1671, 1614 cm- ¹ . [a] o = + 107 ° ic = 1.0) UV spectrum X _max = 240, 311 ηΐμ, (log ε = 3.91, 3.82).

Example 8

80 mg ^^, o-dioxo-nß-acetoxy-A-nor-B-homoandrosten are dissolved in 20 ml of ethanol and mixed with a solution of 0.5 g of Rupfer acetate and 2 g of sodium acetate in 20 ml of water. The reaction solution instantly turns green. After 15 minutes it is poured into water and extracted with benzene. Evaporation of the organic phase in vacuo results in 94 mg of green crystals which, according to the thin-layer chromatogram (mobile phase: benzene-methanol [19: I]) are uniform. After three crystallizations from methylene chloride-methanol, 40 mg of the copper complex of A ^l -l>, (> - Oio \ o-Vlß-a.cet oxy-A-nor-B-homo-androsten, which rises at 300 to 310 ° decomposed. UV spectrum: A _max = 332ηαμ (log ε = 4.14), 246 ΐημ (log ε = 4.31). UV spectrum (CHCl ₃ ): ν = 1721, 1595, 1565, 1498, 1260 cm- ¹ .

Example 9

580 mg of S ^ -dioxo-nß-acetoxy-A-nor-B-homo-androstane are acetylated for 4 days in acetic anhydride-pyridine (1: 1) mixture at room temperature. After evaporation of the reaction solution in vacuo and filtration of the crystalline residue in benzene-ether (9: 1) solution through silica gel, z. ⁵ -3-Oxo-6,17-diacetoxy-A-nor-B-homo-androstene, which, after being redissolved three times from acetone-hexane, melts constantly at 147 to 149 ° (425 mg). UV spectrum: X _max = 254πΐμ (log ε = 3.87). IR spectrum (CHCl3): »= 1745, 1720 (strong), 1638, 1255, 1160 cm- ¹ . [a] ₀ = -10 ° (c = 1.0).

Example 10

80 mg S ^ -Dioxo-nß-acetoxy-A-nor-B-homo-androstane are dissolved in 20 ml of ethanol and mixed with a solution of 0.5 g of copper acetate and 2 g of sodium acetate in 20 ml of water. The solution, which immediately turns green, is poured onto water after 15 minutes, and 90 mg of green crystals are isolated with benzene, which are uniform according to thin-layer chromatogram (mobile phase: benzene-methanol [19: I]). After five crystallization from methylene chloride-methanol, the copper complex of 3,6-dioxo-17 / S-acetoxy-A-nor-B-homo-androstane thus obtained decomposes at 300 to 310 °. UV spectrum: l _max = 310ηαμ (log ε = 4.33), 259 ΐημ (log e = 3.95). IR spectrum (CHCl ₃ ): ν = 1720, 1578, 1475, 1260 cm- ¹ .

Example 11

300 mg of 3,6-dioxo-17 (S-hydroxy-A-nor-B-homo-androstane are heated with 2 ml of hydrazine hydrate in 10 ml of ethanol in a sealed tube for 16 hours at 210 °. The cooled solution is then dried in vacuo evaporated and the crystals obtained (300 mg), which are uniform according to thin-layer chromatogram (mobile phase: benzene-methanol [10: I]), recrystallized twice from methanol to give the pyrazole derivative of 3,6-dioxo-17 ^ -hydroxy-A -nor-B-homoandrostane with a constant temperature of 152 to 155 °. [a] _D = + 57 ° (c = 0.52). IR spectrum (CHCl ₃ ): ν = 3630, 3640, 1635 cm " ¹ ( weak) UV spectrum hnax = 227 Πΐμ, log ε = 3.74.

Example 12

9 g zl ^ -S-Oxo-na-methyl-n / S-hydroxy-androstadiene are in a solution of benzoperic acid in 140 ml of chloroform (35 mg / ml) for 4 days in the dark left to stand at room temperature. The reaction solution is then diluted with ether and successively with aqueous potassium iodide and sodium thiosulphate solution shaken. 9.1 g of crude product are obtained, which is chromatographed on neutral aluminum oxide (activity III; thirty times the amount) will.

Benzene and benzene-ether (9: 1) mixture elutes 1830 mg of amorphous material, which is chromatographed again on neutral aluminum oxide (activity III; 60 times the amount). This gives 1015 mg of crystalline material with a benzene-ether (9: 1) mixture which, after crystallizing twice from acetone-petroleum ether, melts at 165 ° to 167 ° (800 mg). [α] ₀ = 105.1 ° (c = 0.56). UV spectrum: A _max = 232 ηΐμ (ε = 9000). IR spectrum: ν = 3600, 1674, 1617 cm- ¹ .

There is a mixture of 85% 3-Oxo-4 / S, 5 | 8-oxido-17 / S-hydroxy-17a-methyl-zl ¹ -androsten and 15% 3-Oxo-4a, 5a-oxido-17 / S-hydroxy-17a-methyl- ^ l ¹ -androsten before. The ether fractions from both chromatograms yield 5.3 g of unchanged starting material after a single crystallization from acetone-petroleum ether.

700 mg of the above mixture are irradiated in 200 ml of Dibxan for 46 hours. The solution is then evaporated in vacuo. Twice reprecipitation of the crystalline crude product gives 458 mg zl ¹ - 3,6 - dioxo- 17a-methyl -170-hydroxy A-nor-B-homo-androsten with a melting point of 126 to 128 °. [α] ₀ = + 79.8 ° (c = 0.49). UV spectrum _{:; ΐ Β} , « _Β = 239πΐμ (ε = 8200) and 311 ηΐμ (ε = 6700). IR spectrum: ν = 3610, 1761, 1708 cm- ¹ .

Example 13

Under the conditions given in Example 1, d), the bis-methylenedioxy compound of prednisolone becomes 17.20; -Bismethylenedioxy compound obtained from zl ¹ -3,6,20-trioxo-11j3,17a, 21-trihydroxy-A-nor-B-homo-pregnen. After hydrolysis, this gives the free / ^ - 3,6,20-TnOXO-11 / ?, 17α, 21 - trihydroxy - A - nor - B - homo - pregnen; F. = 217 to 224 °.

609 539/432

Example 14

200 mg of S ^ -Dioxo-IV ^ -acetoxy-A-nor-B-homo-androstane are dissolved in 10 ml of glacial acetic acid saturated with hydrochloric acid, and 2 ml of methyl mercaptan are added. After 48 hours, the product is worked up, the zl ³ ' ⁵ ' -3-methylmercapto -6-OXO-17/9-acetoxy -A-nor-B-homoandrosten having a temperature of 166 ° to 167 ° in a practically quantitative yield. [a] _B = + 124 ° (c = 0.67). UV spectrum: A _maa; = 319m ^ (log £ = 4.02). IR spectrum (CHCl ₃ ): ν = 1720, 1624, 1255 cm- ¹ .

Example 15

250 mg / l ^ -S-Oxo ^ n-diacetoxy-A-nor-B-homoandrostadiene are hydrogenated in 20 ml of benzene with 250 mg of 5% palladium carbon. Hfe uptake: 25 ml in 20 minutes. The solution freed from the catalyst is evaporated in vacuo and the residue is chromatographed on 7 g of acidic Al2O3 (activity II). With a hexane-benzene (1: I) mixture, 85 mg of crystals are isolated which, after being dissolved twice from ether-pentane and sublimation, melt in a high vacuum at 139 ° to 140 °. [a] _D = -112 ° (c = 0.49). The preparation is the pure 3-Oxo-17 /? - acetoxy-A-nor-B-homo-androstane, mp 139 to 140 ° C.

Example 16

150 mg of zl ⁵ -3-oxo-6,17 ^ -diacetoxy-A-nor-B-homoandrosten are hydrogenated in 5 ml of benzene in the presence of 150 mg of 5% palladium-on-carbon. The result is a mixture which is chromatographed on 5 g of acidic Al2O3 (activity II). Hexane-benzene (1: I) mixture yields 50 mg of 3-oxo-17 (3-acetoxy-A-nor-B-homo-androstane, which is redissolved twice from ether-pentane and sublimed in a high vacuum; F. 139 to 140 °. [O] "= -116 ° (c = 0.43). IR spectrum (CHCl ₃ ): Amea: = 1727, 1258 cm- ¹ . The compound is identical to the preparation described in Example 15 .

Example 17

10 mg of S-oxo-n ^ -acetoxy-A-nor-B-homo-androstane are left in saturated methanolic KOH solution for 48 hours at room temperature. After working up, 8 mg of 3-oxo result. 17/3-hydroxy-A-nor-B-hoino-androstane, which melts at 129 to 130 ° after being redissolved four times from acetone-hexane. IR spectrum (CHCl ₃ ): k _max = 3620, 1725 cm- ¹ .

B e i s ρ i e 1 18

1.5 g / l of ¹ -3,20-dioxo-4,5-oxido-17a-acetoxy-pregnen in 500 ml of dioxane are irradiated for 72 hours with a low-pressure burner (temperature: 26 to 29 °) and the solution is then in vacuo evaporated. The residue is dissolved in 50 ml of alcohol, diluted with 150 ml of ether and shaken in a separating funnel with 10 ml of ice-cold 10% sodium hydroxide solution in 50 ml of water. After exhaustive extraction with sodium hydroxide solution, the alkaline extracts are combined and acidified with dilute hydrochloric acid, with 850 mg of crude / ^ - 3,6,20-TnOXO-na-acetoxy-A-nor-B-homo-pregnen being obtained. After crystallization from methylene chloride-ether, the pure compound melts at 198 to 199 °, [a] _D = + 76 ° (c = 0.945). A single spot is visible in the thin-layer chromatogram (system: benzene-methanol 9: 1).

The portion that does not react with sodium hydroxide solution is 0.5 g and represents unchanged starting material represent.

The starting material can be prepared as follows: 10 g / l of ⁴ -3,20-dioxo-17a-acetoxy-pregnen are dissolved in 100 ml of methylene chloride and 300 ml of methanol and added dropwise at 0 ° with 60 ml of 30% hydrogen peroxide and 20 ml of 10% sodium hydroxide solution are added and the mixture is stirred at 0 ° C. for 27 hours. The reaction mixture is then poured onto ice-water and extracted with methylene chloride and ether. After washing neutral, drying and evaporation in vacuo, 9 g of crude 3,20-dioxo-17a-acetoxy-4,5-oxido-pregnane are obtained, which is used for the next step without further purification.
5.16 g of crude 3,20-dioxo-17a-acetoxy-4,5-oxidopregnane are dissolved in 75 ml of tert-amyl alcohol. After adding 2.5 ml of glacial acetic acid and 0.5 g of mercury, the mixture is heated to boiling and, with thorough stirring, a solution of 2.5 g of selenium dioxide in 32 ml of tert-amyl alcohol is added dropwise. After 14 hours it is cooled, suction filtered over a layer of Norit and the filtrate is evaporated in vacuo. The residue is taken up in ethyl acetate and washed successively with 10% strength potassium iodide solution, 20% strength sodium thiosulfate solution, 10% strength sodium carbonate solution and water. After evaporation of the solvent, 5.78 g of crude zI ¹ -3,20-dioxo-4,5-oxido-17a-acetoxy-pregnen are obtained, which after filtration over aluminum oxide (activity II) and crystallization from methylene chloride-ether at 203 melts up to 212 °.

Example 19

1 g of zl ¹ -3,6,20-trioxo-17a-acetoxy-A-nor-B-homopregnene are hydrogenated in 100 ml of benzene in the presence of 1 g of 5% palladium-on-carbon. After the amount of hydrogen calculated for 1 mole has been taken up, the catalyst is filtered off and evaporated. The residue represents the S ^^ O-trioxo-na-acetoxy-A-nor-B-homo-pregnane, which melts after crystallization from ether at 221 to 224 °; [a] ₀ = + 2 ° (c = 0.164).

In an analogous manner, the z) ¹ -3,6-Dioxo-17a-methyl-17 ^ -hydroxy-A-nor-B-homo-androstene described in Example 12 becomes 3,6-Dioxo-17a-methyl-17 / i-hydroxy-A-nor-B-homo-androstane reduced from m.p. 158 to 160 °; [a] ₀ = + 34 ° (c = 0.921).

Example 20

4.15 g ^ l ¹ -3-oxo-4,5-oxido-17a-methyl-17 ^ -acetoxyandrosten in 500 ml of dioxane are irradiated for 72 hours with a low pressure burner (temperature: 26 to 30 °) and according to the information in Example 18 worked up. The sodium hydroxide-soluble portion is 3.63 g and represents the zl ^^ - Dioxo-na-methyl-17 / S-acetoxy-A-nor-B-homo-androsten, which after crystallization from methylene chloride-ether at 206 to 210 ° melts.

The starting material used for the irradiation can be prepared as follows: <d ⁴ -3-Oxo-17a-methyl-17 /? oxido-17a-methyl-17/9-acetoxy-androstar (m.p. = 119 to 121 °, from acetone-hexane) oxidized.

and then dehydrogenated to zl ^x -3-oxo-4,5 - oxido - 17a - methyl -Π β- acetoxy - androstene by means of selenium dioxide.

Example 21

3 g / l of ¹ -3-oxo-4,5-oxido-20 /? - acetoxy-pregnen in 500 ml of dioxane are irradiated with a low-pressure burner for 70 hours (temperature: 27 ° to 30 °) and worked up as described in Example 18 . The natronlauge soluble portion provides 2.16 g Δ! -3,6-di ίο oxo ^ OSS acetoxy-A-nor-B-homo-pregnene which melts after crystallization from methylene chloride-ether at 161 to 163 °. [al _D = + 134 ° in chloroform (c = 0.511). In addition, 550 mg of starting material are recovered.

The above starting material can be obtained as follows: The ^{I 4} -3-oxo-20j8-hydroxy-pregnen with a melting point of 167 to 170 ° is oxidized with alkaline hydrogen peroxide as described in Example 18, and the crude product obtained is treated with acetic anhydride-pyridine and the 3-oxo-4,5-oxido-20ß-acetoxypregnane is dehydrated by means of selenium dioxide to give J ¹ -3-oxo-4,5-oxido-20 ^ -acetoxy-pregnene.

B e i s ρ i e 1 22

2 g of ¹ -3,6-dioxo-20 ^ -acetoxy-A-nor-B-homopregnene are boiled in 50 ml of saturated methanolic potassium carbonate solution for 32 hours under nitrogen and worked up according to the information in Example 7, with 1.74 g of crude zl ¹ -3,6-Dioxo-20 / S-hydroxy-A-nor-B-homo-pregnen can be obtained, which melts after recrystallization from methylene chloride-ether at 148 to 149 °; [a] _D = -59 ° (c = 0.937).

Example 23

35

800 mg of zl ¹ -3,6-dioxo-20 _i S-hydroxy-A-nor-B-homopregnene are hydrogenated in 200 ml of benzene in the presence of 800 mg of 5% palladium carbon. After the amount of hydrogen calculated for 1 mol has been taken up, the catalyst is filtered off and the filtrate is evaporated in vacuo. The 3,6-dioxo-20 / S-hydroxy-A-nor-B-homo-pregnane obtained after crystallization from ether-pentane melts at 117 to 118 °.

Example 24

45

1.5 g of lactone des zl ¹ -3-oxo-4,5-oxido-17 ^ -hydroxy-17a- (j3-carboxyethyl) -androstens in 500 ml of dioxane are 72 hours with a low pressure burner (temperature: 26 to 29 ° ) irradiated, the solution then evaporated in vacuo and worked up as in Example 18. The caustic soda extract represents the lactone of the zl ^^ - dioxo-nß-liydroxy-na-dS-carboxy-ethyl) -A-nor-B-homo-androstens; after crystallization from methylene chloride-ether it melts at 185 to 186 °, [a] = + 85 °.

The lactone is obtained therefrom by catalytic hydrogenation as described in Example 2 of 3,6-Dioxo-17ß-hydroxy-17ct - (/ S-carboxyethyl) -A-nor-B-homo-androstans, which melts at 193 to 194 ° after dissolving from methylene chloride-ether. The A-nor-B-homosteroids obtained are also diuretically active and show an anti-aldosterone effect.

The starting material can be obtained from the lactone of the zl ⁴ -3-oxo-17 ^ -hydroxy-17a-dS-carboxyethyl) -androsten by oxidation with hydrogen peroxide and subsequent dehydrogenation using selenium dioxide as described in Example 18.

Example 25

On irradiation of the zl ¹ -3-oxo-4,5-oxocholester, which is obtained according to Example 18 from the corresponding J ⁴ -3-ketone, the z ^ - ^ o-dioxo-A-nor-B- homo-cholesten, m.p. 97 ° (from pentane).

Example 26

1.5 g of zl ¹ -3,20-dioxo-4,5-oxido-11 ^, 17a-dihydroxy-21-acetoxy-pregnen are irradiated and worked up according to the information in Example 18, the Δ ^{1 -3.6} , 20 - Trioxo - 110,17a - dihydroxy - 21 - acetoxy-A-nor-B-homo-pregnen and the Λ ^, ό ^ Ο-Τποχο-ΙΙ & Πα ^ Ι-ΐπην-droxy resulting from partial hydrolysis during the sodium hydroxide extraction -A-nor-B-homo-pregnen are obtained; F. = 217 to 224 °.

According to the information in Example 2, the irradiation products described can be converted into 3,6,20-trioxo-II / ?, 17a-dihydroxy-21-acetoxy-A-nor-B-homo-pregnane or the 3, 6.20 - trioxo - Uß, 17a, 21 - trihydroxy - A - nor-B-homo-pregnane transfer; F. = 132.5 to 138 °.

The starting material used above is obtained from z1 ¹ ' ⁴ -3,2O-dioxo-110,17a-dihydroxy-21-acetoxypregnadiene by reaction with benzoperic acid as described in Example 1, a).

Example 27

1.8 g of the 17.20; 20.21-bis-methylenedioxy derivative of prednisolone are in a solution of benzoperic acid in 110 ml of chloroform (45 mg / ml 7 days left in the dark at room temperature. The reaction solution is then diluted with ether and successively with aqueous potassium iodide and sodium thiosulphate solution, water, sodium hydrogen carbonate solution and washed again with water. After evaporation, 1.4 g of a mixture containing the 17,20; 20,21-bismethylenedioxy derivative are obtained of 4α, 5α- and 40,50-oxidoprednisolone obtain.

1.4 g of the above mixture are exposed to a low-pressure mercury lamp in 170 ml of dioxane for 14 hours. After working up as described in Example 18, 420 mg of the 17.20; 20.21-bis-methylenedioxy derivative of A ¹ S ^, 20 - trioxo -1 1, 17 ct, 21 - trihydroxy - A - nor - B - homopregnate are obtained which, after filtration through silica gel, decolorization with animal charcoal and crystallization from acetone-petroleum ether, melts at 210 to 230 ° with decomposition; [a] _D = -7 ° (c = 0.7). UV spectrum: Xmax = 236 or 310 ΐημ (ε = 8000 or 6080).

Claims (3)

Patent claims: 1. A process for the preparation of A-nor-B-homosteroids, characterized in that that you have a 3-oxo-4,5-oxidosteroid, possibly under temporary Protection of groups that are not inert under the reaction conditions with ultraviolet light irradiated in the presence of an organic solvent and, if desired, the obtained 3,6-Dioxo-A-nor-B-homo-steroid in a manner known per se in its functional, from the Enol form derived ketone derivatives, in particular especially with acylating agents in the corresponding 6-enol acylates, converted and / or converted into its metal salts, especially copper complexes, or reacted with hydrazines and, if desired, obtained z) ⁵ -3-oxo-6-acyloxy-A - nor - B - homo - steroids catalytically hydrogenated or obtained A-nor-B-homo-steroids with functionally modified hydroxyl and / or keto groups hydrolyzed. 2. The method according to claim 1, characterized in that the irradiation in dioxane executes. 3. Process according to claims 1 and 2, characterized in that 3-Οχο-4α, 5α- or -4 / 3.5 / S-oxido-steroids, in particular 3-oxo-4,5 - oxido - androstane or -19-nor-androstane or their 1-dehydro derivatives, 3-oxo-4,5-oxidopregnane or -19-nor-pregnane or their 1-dehydro derivatives, 3-oxo-4,5-oxido-cholestane or -spirostane or their 1-dehydroderivate or 1-dehydro-4,5-oxido-testololactone or the lactone of Δ ¹ - 3 - oxo - 5 - oxide ^ o - Π β - hydroxy-17a- (j8-carboxyethyl) -androstens used as starting materials. 609 539/432 3.66 © Bundesdruckerei Berlin