DE1076685B - Process for the synthesis of 11, 18-dioxigenated 16-oxoandrostane compounds - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

kl. 12 ο 25/04

INTERNAT. KL. C 07 C

PATENT OFFICE

EXPLAINING PUBLICATION 1076 685

C 17941 IVb / 12 ο

REGISTRATION DATE: NOVEMBER 27, 1958

NOTIFICATION OF THE REGISTRATION AND ISSUE OF THE EDITORIAL:

MARCH 3, 1960

Among the 18-oxygenated steroids, particularly possesses the hormone aldosterone, which is isolated from the adrenal glands, because of its specific effect on mineral metabolism outstanding meaning. But since on the one hand the amounts occurring in animal organs for an economic Extraction of the hormone are too low and on the other hand it was not previously possible to take aldosterone from To prepare other, naturally occurring steroids partially synthetically, shows the totally synthetic production great technical interest.

A new process has now been found by means of which aldosterone and its derivatives can be obtained in a simple manner from an A *> ¹⁸ -3,16-dioxo-II / S, 18a-oxido-18a-methyl-18-homo-androstadiene the formula

or to build up a corresponding 3-ketal, which also a further double bond in the 14,15 position may have.

The new process can be divided into four main parts:

A. Degradation of the cyclic enol ether grouping on ring C to give the 18,11-cyclohemiacetal structure typical of aldosterone.

B. Condensation with an oxalic acid ester in the 7-position and preparation of derivatives for protecting the 20-oxo group.

Method of synthesis

11,18-dioxigenated 16-oxoandrostane

links

Applicant: CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority: Switzerland of December 5, 1957

Dr. Albert Wettstein, Dr. Georg Anner,

Dr. Karl Heusleor, Basel,

Dx. Hellmut Uebexwasser, Riehen,

Dr. Peter Wieland, Dr. Julius Schmidlin

and Dr. Jean-Rene Billetex, Basel (Switzerland), have been named as the inventor

C. Hydrogenation of the 14,15 Double Bond and Elimination the oxygen function in position 16.

D. Conversion of the side chain into the ketol side chain of aldosterone.

An embodiment of the synthesis is compiled in the following equation:

Part A

AcO CHO

NaJO ₄

Pyridine
O + track0s0 ₄

Well,

909 758/550

(Ί

Η, —Pd

OH

VI

ALO ₃

^N 0 '!

ο-

OH

ο—!

IV

IvV

VII

[NaH (COOCH ₃ ) ₂

TeüB

Lo COOCH Ό ^Χ tj O

Χ ^ o OH

XI

Part D.

COOCH ₃

CO LiAlH,

0 0

CH ₂ OH

- O CH ₂ OAc

CHOH Ac ₂ O-pyridine

O O

CHOH

XIV

XVI

CH ₉ OAc

CrO ₃ - pyridine

O CH ₂ OAc

XVII

Aldosterone monoacetate

The process according to the invention relates to part A of the reaction sequence described above, that is to say the degradation of the cyclic enol ether to the IS.II-CycIohemiacetal. The procedure is that one in one

androstadien of the formula

which is a further double bond in the 14,15 position may have or in a corresponding 3-ketal cleaves the 18,18a double bond oxidatively and in the obtained II / S-acetoxy-18-oxo compound the II /? - acetoxy group saponified under alkaline conditions, with this or the 16-oxo group temporarily in the presence of a 14 (15) double bond is protected by known methods, and optionally modifies the function of the hemiacetal group and, if desired, the 14 (1 S) double bond in a known manner at the corresponding reaction stage hydrogenated.

The splitting of the 18,18a-enol double bond takes place z. B. in that for the oxidative cleavage of double bonds well-known way. The ozonides obtained through the action of ozone become reductive, z. B. split with zinc and acetic acid. The cleavage even succeeds by oxidation with compounds of the 6-valent chromium, e.g. B. with chromic acid in pyridine. But it is also possible to have the enol double bond in itself known manner to hydroxylate, for. B. by the action of molar amounts of osmium tetroxide, and the resulting To split glycols with periodic acid, lead tetraacetate or sodium bismuthate. Particularly advantageous a new, extremely mild hydroxylation method has proven itself. It consists in doing the oxidation with an alkali metal periodate, e.g. B. sodium periodate, in the presence of a catalytic amount Osmium tetroxide with the addition of an alkali salt of a carboxylic acid, e.g. B. potassium acetate, in an aqueous Medium. In this way, the glycol is obtained in a practically quantitative yield, which is mixed with periodic acid can split. If pyridine is used as a buffer instead of potassium acetate, the glycol is not produced, but directly the llß-acetoxy-l 8-oxo compound.

The saponification of the 11/9 acetoxy group succeeds even under relatively mild conditions because of the presence of the 18-oxo group. It can e.g. B. an alkali metal carbonate, e.g. B. potassium carbonate, in aqueous methanol or dioxane or sodium methylate in absolute methanol can be used. Temperatures of around 20 ^° C. are usually sufficient for the reaction to end in a few hours. The II / I-hydroxy-18-oxo compounds obtained in the saponification are present, at least in solution, almost entirely as cyclohemiacetals.

The free hydroxyl group of the cyclohemiacetal can, if desired, esterified, etherified or to form the oxo group are oxidized. The esterification takes place in a manner known per se with reactive derivatives of Carboxylic acid, such as acid anhydrides or halides in the presence of acid-binding agents, e.g. B. pyridine. It can be z. B. acetic acid, propionic acid or butter

7 8

acid anhydride, BenzoylcMorid or Trimethylessigsäure- sators on a carrier, z. B. animal charcoal, calcium chloride use as an esterifying agent. The 18-ester carbonate, barium sulfate or zinc carbonate, for 14-hydration also by transesterification, e.g. B. opened by heating oxy compound. Then the 14,15-Dopeines 18-ester of a low-boiling acid, with a pelbind by dehydration from the 14-hydroxy salt a higher boiling acid, such as a tertiary 5 16-ketone re-introduced. The elimination of water will Amine, e.g. B. triethylamine salt win. advantageously carried out under alkaline conditions.

The etherification is advantageously weak in the presence. Salts such as dehydrating agents can also be used acidic condensing agents such as ferric chloride or piperidine benzoate or acetate or triethylamine benzoate Pyridine hydrochloride. As an ethereal question. The elimination of water succeeds particularly well medium come orthoformic acid esters, z. B. Ortho- ίο by heating with aluminum oxide in an inert Formic acid methyl ester, ethyl ester or benzyl ester, solvents such as benzene, toluene and the like but especially dihydropyran into consideration. Both the temporary protection and the retrospective Both the esters and the ethers are very easy to split again, so the 14 (15) double bond is reintroduced for example, by brief heating in an aqueous one of considerable importance because namely found Carboxylic acid, e.g. B. aqueous acetic acid. The esters can 15 was that the steric course of the catalytic can also be broken down by mild alkaline saponification. Surprisingly, hydrogenation of this double bond

The cyclohemiacetal group is easily dependent on the substitution at carbon atom 18 for lactone oxidize group. These are compounds of the 6-valent is. When used as starting materials of the invention Chromium, e.g. B. chromic acid in pyridine, chromic acid in ice process and cyclic enol ethers used in vinegar, sodium dichromate, but also other oxidizing agents through oxidative cleavage of the enol double bond medium, e.g. B. manganese dioxide, suitable. obtained ll ^ -Acetoxy-18-oxoverbindungen arise

If the cleavage made of the cyclic enol ether at a in the catalytic hydrogenation mainly the "unna- ^ J ¹⁴ -16-keto compound, then the encryption-natural" 1 ^ compounds. On the other hand, the soaping of the 11S-acetoxy group does not provide previous / I ¹⁴ -16-oxo compounds with 18,11-cyclohemiacetal or protection of the. sensitive vinylogous / 3-keto-aldehyde-25 18,11-lactone groups practically exclusively the natural grouping of the resulting J ¹⁴ -11 /? -acetoxy-16,18-dialhen 14a compounds with trans-linked rings C oxo compound take place. This can e.g. B. by Ketali- and D. To achieve high yields of 14a-versation of one of the two oxo groups with a 1,3- or bonds, it is therefore advantageous to use the 18,11-Cyclohemi-1,2-glycol, eg. B. ethylene glycol or propylene glycol, or acetal grouping before the hydrogenation of the 14,15-double conversion into a thioketal or hemithioketal, 30 to introduce a bond.

z. B. with ethylene mercaptan or mercaptoethanol, in / 1 ⁴ -3,16-dioxo compounds can, if desired,

Presence of a ketalization catalyst, e.g. B. pyridine by ketalization with methyl-ethyl-dioxolane in counter-hydrochloride, take place. With ethylene glycol z. B. was catalytic amounts of p-toluene sulfonic acid in an 18-ketal, with ethylene mercaptan a 16-thioketal. 3 monoketals are transferred, as has already been done in The thioketals are described for temporary protection in 35 patent 1,011,883.

particularly suitable because they are z. B. with the help of mercury 11,18-dioxigenated saturated in the 14,15-position

silver or cadmium salts selectively, ie while maintaining zJ ⁴ -3,16-dioxo-androstenes, especially their 3-ketals, other ketal groups, e.g. B. in the 3-position, again to can, as indicated above and in the examples, be split into ketone. the corresponding 18,11-lactones carry over. In these

It is also possible, however, to ^{convert the ZT 14} -16-oxo grouping 40 according to the method of the German interpretation before the oxidative cleavage of the enol double bond as in writing 1,061,778 by condensation with a ^{carbon that the sensitive / l 14} -r8-oxo-16 -ketonic acid ester introduce a 17-carbalkoxy group. Enolgar does not occur as an intermediate product in the further conversion acetylation and hydrogenolytic removal of the enolungen. You can z. B. in the starting material the acetate group leads to the 16-unsubstituted etioic acid-16-keto group with a complex metal hydride, e.g. B. 45 ester, the conversion of which into aldosterone is described in the patent lithium aluminum hydride, lithium borohydride or Na-1,018,861.

trium borohydride, reduce to carbinol. By oxy- The compounds that can be prepared according to the invention are

Dative cleavage of the enol ether double bond, as indicated above, valuable intermediates for the preparation of Aldo, one obtains a Δ "-11 / J-acetoxy-18-oxosterone and its derivatives.

16-hydroxy compound, which then leads to the cyclohemi- 50 In the compounds obtained according to the method acetal can be saponified. Subsequently, z. B. with it concerns racemates or optically active Ver manganese dioxide, the 16-hydroxy group bonds to the 16-oxo group. Racemates can be carried out in a manner known per se oxidized. are split into optically active compounds.

A particularly advantageous reaction sequence for producing The starting materials for the process according to the invention

position of the cyclohemiacetal derivatives (esters and ethers) 55 are described in patent 1,011,883,
von / l ¹⁴ -lljS-Hydroxy-16,18-dioxo-androstenen under Ver. The process according to the invention also includes the use of an epoxy for the protection of the 14 (15) -duplicate forms, in which only part of the process link is in the formula scheme Introduction shown. measures and these, if necessary, in a different series-This reaction sequence consists in that one can be carried out as a sequence or whereby one can obtain from a 3-ketal des, d ⁴ > ¹⁴ > ¹⁸ -3,16-di-60 of any process stage used in the starting material Intermediate prooxo-lljS.lSa-oxido-lSa-methyl-lS-homo-androstatriens duct runs out and the remaining process is carried out with hydrogen peroxide in alkaline solution in the stage. Corresponding 14,15-epoxy is transferred in the following examples. It is explained in more detail above. Surprisingly, the temperatures in degrees Celsius are not affected by the enol double bond. specified.

In the epoxy obtained, the 18,18a-enol double 65 Beismel 1

bond, as stated above, oxidatively split and the

lljS acetoxy group saponified. Before or after the treatment To a solution of 340 mg d, l-Zl ⁴ > ¹⁸ -3,16-Dioxo-

Esterification or etherification of the cyclohemiacetal group II / 3,18a-oxido-18a-methyl-18-homo-14-iso-androstadiene is then the 14,15-epoxide by catalytic hydrogenation in 20 cm ^{3 of} absolute tetrahydrofuran and 0.22 cm ³ Pyrrung, preferably in the presence of a palladium catalyst, a solution of 290 mg is added with stirring

9 10

Osmium tetroxide in 10 cm ^{3 of} absolute ether. After mixing 10 cm ^{3 of} water, 20 cm ^{3 of} pyridine and 10 cm ^{3 for} 1 hour, the stirrer is switched off and the reaction glacial acetic acid is left to stand overnight at room temperature with 15 g of zinc dust in the form of a dilute acetic acid activated, water-moist porridge, whereby the adduct crystallizes out, which after the addition The temperature rises temporarily to -5 °. of 100 cm ^{3 of} methanol, however, dissolves again. After cooling down again to -7 °, the unguided zinc is sucked off with stirring with a solution of 4 g of ammonium and rinsed with benzene, sulfite in 100 cm ^{3 of} water and after ^{1 1} ₂ hours with the filtrate is washed several times with water, then with diatomaceous earth (known under the trade name of 10% sodium hydrogen carbonate solution, four times with CeHt), in order to bring the precipitate formed into easily filterable 100 cm ^{3 of} ice-cold 1,5N phosphoric acid and again with form. After filtering through a "Celite" water, finally with hydrogen carbonate solution. After the layer and washing with 500 cm ³ of methanol is dried, the solvent are removed in vacuo, the filtrate in vacuo at 50 to 60 ° to about 50 cm ³ from the crude product crystallized on addition of concentrated and washed four times with 50 cm ³ of a 7 Parts of 2 cm ^{3 of} methylene chloride and 10 cm ^{3 of} ether 3.3 gd, 1A ⁵ · ¹⁴ -3-chloroform and 3 parts of alcohol consisting of a mixture of ethylenedioxy-11ß-acetoxy-16,18-dioxo-androstadiene, extracted. The chloroform-alcohol extracts are shaken 15 which after dissolving from benzene at 188 to 189 ° one ^{melts individually with 60 cm 3 of} semi-saturated saline solution.

the end. The residue (320 mg) of the dried and one IR spectrum in CH ₂ Cl ₂ : no OH band; 3.7μ (Alde-

evaporated organic solution in 7.5 cm ^{3 of} methanol hyd); broad band at 5.75 to 5.82 μ with inflection at and 1.25 cm ^{3 of} pyridine dissolved and with 1.5 cm ³ a 5.9 μ (ester, aldehyde, 16-CO); 6.22 µ (A ¹⁴ ); 8.16 μ 0.912 n-periodic acid solution added. After 1 hour 20 (acetate); 9.1 µ (ketal). UV spectrum: e _238m ^ = 12900. Leave to stand at room temperature and add. .

50 cm ^{3 of} semi-saturated sodium chloride solution are extracted from Example ό

four times with 50 cm ^{3 of} chloroform. The residue of the 500mg d, l-Zl ⁵ > ¹⁸ -3-ethylenedioxy-ll / ?, 18a-oxido-16-oxo-

50 cm ^{3 of} semi-saturated sodium chloride solution, 18a-methyl-18-homo-14-iso-androstadiene are mixed with dried and evaporated chloroform in a vacuum, stirring and ice-cooling to give 500 mg of chromium trioxide in 6 cm ³ solutions is added to 9 g of aluminum oxide ( Activity II) given to absolute pyridine. Chromatographed after stirring for 20 hours. In benzene, ether and ether at room temperature is treated with semi-saturated Essigester-9: 1-eluates is the d, l-Zl ⁴ -3.16, brine and benzene and filtered through "Celite". 18-Trioxo-II / 3-acetoxy-14-iso-androstene (146.5 mg), which is first washed with benzene and then with water after redissolving from acetone-ether at 161 to 165.5 ° 30 and then the aqueous Phase of the melts. The IR spectrum (solvent: CH ₂ Cl ₂ ) of the filtrate was extracted twice with benzene. The back shows the following bands in the carbonyl region: 3.67 μ was the twice with half-saturated saline solution (aldehyde); 5.72 µ, broad (aldehyde + ester -f- 5-ring-CO) washed, dried and evaporated in vacuo and 5.96 µ + 6.15 µ (α, β unsaturated CO). Benzene solutions are chromatographed on 15 g of aluminum

A solution of 25 mg of the above 11 ^ -acetate and 35 miniumoxide (activity II). The first benzene fractions contain 100 mg of potassium carbonate in 6 cm ^{3 of} alcohol and 3 cm ^{3 of} starting material. The later benzene-water will eluate under reflux for 1 hour in a stream of nitrogen containing the d, l-Zl ⁵ -3-ethylenedioxy-16,18-dioxo-boiled. It is then poured onto semi-saturated sodium chloride II / S-acetoxy-14-iso-androsten, which, after dissolving from the solution and extracted once with benzene and three times with ether, melts at 171 ° to 172 °. The IR spectrum with chloroform. The residue of the saturated 40 (solvent: CH ₂ Cl ₂ ) shows the following characteristic sodium chloride solution, dried and single bands: 3.68 μ (aldehyde); 5.75 μ, intensive (aldehyde-evaporated organic solutions give after dissolving from + 5-ring CO + ester); 8.14 µ (acetate) and 9.15 µ acetone - ether the d, ^{1- ^ 4} -3,16,18-trioxo-II / 9-hydroxy- (ketal).

M-iso-androstene-cyclohemiacetal from melting point 221 to Beismel 4

226 °. In the IR spectrum (solvent: CH ₂ Cl ₂ ) the 45 ^p

Aldehyde band at 3.67 μ disappeared. An charak- 1.0 gd, l-Zl ^{5 '18} -3-ethylenedioxy-ll / ?, 18a-oxido-16-oxo-

teristic bands, it shows a hydroxyl-18a-methyl-18-homo-14-iso-androstadiene at 2.78 μ, dissolved in 5 cm ³ band, at 5.72 μ the 5-ring ketone band and at 5.97 pyridine and 50 cm ^{3 of chloroform, the bands for the Zl 4} -3-ketone, indicated in Example 2 and 6.17 μ, for 33 minutes with an ozone

The saponification is also successful if a solution 50-containing oxygen stream of 5.28 mg ozone minutes of 41.8 mg of the 11/3 acetate and 54 mg of potassium carbonate is treated and in the manner described there in 6.5 cm ^{3 of} methanol and 1 , 75 cm ^{3 of} water worked up for 22 hours. The thus obtained d, lA ⁵ -3-ethylenedioxy in an evacuated ampoule at room temperature ll /? - acetoxy-16,18-dioxo-14-iso-androsten is left with the im. Example 3 described compound completely identical.

Example 2 ^ The same connection can also be derived from the

game 2 described d, l-Zl ^B > ¹⁴ -3-Äthylendioxy-ll /? - Acet-

7,0g d, l-zl ⁶ ' ¹⁴ ' ¹⁸ -3-ethylenedioxy-ll / ?, 18a-oxido-16-oxo-oxy-16,18-dioxo-androstadiene as follows: 18a-methyl-18-homo -androstatrien, dissolved in 10 cm ³ dry 400 mg of this compound are in 60 cm ^{3 of} fine spirits

kenem pyridine and 80 cm ^{3 of} chloroform, are treated at -15 at normal pressure and room temperature with use -18 ° for 28.5 minutes with turbines with 60 manure of 200 mg of 10% palladium-carbon catalyst in an ozone-containing oxygen stream, which hydrogenates sator. After the reaction mixture has absorbed about 1 molar equivalent of 24.5 mg of ozone per minute, hydrogen (about 10 hours) results in the hydrogenation. The first sample through which the exhaust gases flow comes to a standstill. The solution, filtered off from the catalyst, of a mixture of 0.5 cm ^{3 of} O2N thiosulfate solution, is evaporated in a water-jet vacuum. The Rohcm ³ 10 ° / ₀ potassium iodide solution, 0.5 cm ³ starch solution 65 product shows bei233m _/ w still an absorbance of 0.5 cm ³ and 2n-acetic acid turns 28 minutes 4400 (about 30% Zl ¹⁴ -16- Ketone) and is attached to 12 g of aluminum brown violet; the envelope of the subsequent second miniumoxide (activity II) is chromatographed. The sample takes place after 30 seconds. Then you displace with benzene and benzene-ethyl acetate 9: 1 mixture, elute the oxygen with nitrogen and reduce the formed fractions can through crystallization from methanol deten ozonide (after adding a pre-cooled to -10 ° 70 a total of 195 mg ά, Ι- Α ⁵ ~ 3-ethylenedioxy-ll /? - acetoxy-

I 076 685

16,18-dioxo-14-iso-androstene with a melting point of 171 ° to 172 ° can be isolated. The fractions eluted with benzene-ethyl acetate 2: 1 mixture after evaporation and crystallization from methylene chloride-ether yield 40 mg ά, Ι-Δ ⁵ -3-ethylenedioxy-II / I-acetoxy-Lö-oxo-IS-hydroxy- ll-isoandrosten of m.p. 226 °.

192 mg of the above-described d, l-Zl ⁵ -3-ethylenedioxy-II /? - acetoxy-16 ₎ 18-dioxo-14-iso-androstene are dissolved in 50 cm ^{3 of} alcohol, with a solution of 800 mg of potassium carbonate in 25 cm ^{3 of} water are added and I ¹ Z is refluxed under nitrogen at a bath temperature of 110 ° for _{2 hours.} The mixture is then cooled, the alcohol is removed in a water-jet vacuum and the aqueous solution is extracted several times with a benzene-ether 1: 1 mixture. The organic extracts washed with water give, after drying and evaporation, 173 mg of a crystallized residue. After recrystallization from acetone-ether and methylene chloride- ether, the d, l-Zi ⁵ -3-ethylenedioxyl / I-hydroxy-lo.lS-dioxo-M-iso-androstene-cyclohemiacetal melts at 208 to 211 °.

IR spectrum in CH ₂ Cl ₂ : bands at 2.79 and 2.95 μ (OH free and assoc.); 5.74 µ (16-CO); no further bands between 5.6 and 6.5 μ; 9.16 µ (ketal).

80 mg of the above hemiacetal are in 1.0 cm ³ abs for 24 hours. Pyridine and 0.5 cm ³ acetic anhydride left to stand at room temperature. It is then poured into 20 cm ^{3 of} ice water and the white, crystallized precipitate is filtered off with suction after 30 minutes. The crude product (87 mg) is crystallized from acetone-ether. The pure hemiacetal acetate melts at 183 to 185 °. .

IR spectrum in CH ₂ Cl ₂ : no O H band; Bands at 5.74µ (strong, ester + 16-CO); 8.15 µ (acetate); 9.13 µ (ketal).

To a solution of 300 mg of chromium trioxide in 3 cm ^{3 of} abs. Pyridine is added while cooling with ice 135 mg of the above-described cyclohemiacetal des d, l-zl ⁵ -3-ethylenedioxy-1 l /? - hydroxy-16,18-dioxo-14-iso-androstene and the mixture is then left for 4 hours stir at room temperature. Then it is poured onto dilute saline solution and extracted with benzene. The mixture is then filtered through "Celite" and the filter residue is washed thoroughly with benzene. The benzene layer is separated off in the filtrate and washed with dilute sodium chloride solution. The aqueous solutions are each extracted again with benzene and the combined benzene solutions are dried and evaporated to dryness under reduced pressure. After crystallization from acetone-ether, the crystallized residue yields 120 mg of the 18,11-lactone of dl-Zl ^ -Athylenedioxy-lljlS-hydroxy-16-oxo-14-iso-androstene-18-acid with a melting point of 196 ° to 197 ° .

IR spectrum in CH ₂ Cl ₂ : bands at 5.62 μ (γ-lactone); 5.71 µ (16-CO) and 9.11 µ (ketal).

Example 5

To a solution of 10 g of sodium borohydride in 200 cm ^{3 of} 70 ° / Qigem methanol is added, while stirring and cooling with ice water in a stream of nitrogen, a solution of 10 gd, l-zl ^s > ^{14 '18} -3-ethylenedioxy-llß, 18a- oxido-16-oxo-18a-methyl-18-homo-androstatriene in 140 cm ^{3 of} tetrahydrofuran and rinsed with 60 cm ^{3 of} tetrahydrofuran. The cooling bath is then removed and stirring is continued overnight at room temperature in a stream of nitrogen, crystals separating out, which, however, dissolve again when ^{200 cm 3 of water are added.} Now it is largely evaporated in vacuo in a stream of nitrogen at a bath temperature of 40 to 50 °, extracted three times with benzene, the benzene solutions are washed three times with water, dried and evaporated in vacuo at 50 °. Finally, it is dried in a high vacuum ^{for 1} Z _{2 hours at 50 °.} Now it is dissolved in 15 cm ^{3 of} dry pyridine and 70 cm ^{3 of} chloroform and an ozonized oxygen stream of 23 mg ozone minute output is allowed to act for 63 minutes at -15 ° with turbines. ^{The color change of a test liquid containing 0.5 cm 3 of} O.02n thiosulfate solution through which the exhaust gases flow takes place after 54 minutes and 35 seconds, the change of a corresponding third test solution after

ίο one minute and 20 seconds. Then the work-up takes place in the manner described in Example 2.

For hydrolysis, the crude ozonization product is dissolved in 11 alcohol, with 500 cm ³ 4 offset ° / ₀ sodium potassium carbonate in water and boiled for 2 hours in a nitrogen stream under reflux. After addition of 15 cm ^{3 of} glacial acetic acid, vigorous concentration in vacuo in a stream of nitrogen at a bath temperature of 55 ° and addition of 2N soda solution, extraction is carried out four times with 250 cm ^{3 of} chloroform. The chloroform extracts are then washed with saturated sodium chloride solution, dried and evaporated in vacuo in a stream of nitrogen. Addition of a benzene-ethyl acetate-ether mixture gives 2.96 g of the 18,11-cyclohemiacetal des d, l- ^ l ⁵ > ¹⁴ -3-ethylenedioxyl / 3,16-dihydroxy-18-oxo-androstadiene in the form of a light brown powder. When the evaporated mother liquor is chromatographed on 60 g of aluminum oxide (activity II), a further 340 mg of this compound are obtained with ethyl acetate and chloroform.
The combined crystals (3.3 g) are ^{mixed with 300 cm 3 of} chloroform and oxidized for 5 hours with 25 g of activated manganese dioxide while stirring at room temperature. After filtering through “Celite”, rewashing with chloroform and evaporating the filtrate in vacuo in a stream of nitrogen, the residue is redissolved several times from acetone. The resulting 18,11-lactone of d, l- ^ ^{5 '14} -3-ethylenedioxy-llj3-hydroxy-16-oxo-androstadiene-18-oic acid melting at 244 to 246.5 °, and shows the following ultraviolet spectrum: First Maximum at 221 πιμ (e = 10050), minimum at 228 ΐημ (ε = 8650); second maximum at 241 πιμ (ε = 11800). In the carbonyl region, the IR spectrum (solvent: CH ₂ Cl _2), the following characteristic bands: 5.6 μ (y-lactone) and 5.81 μ + μ 6.16 (zl ¹⁴ -16-ketone). The residue of the evaporated mother liquor of the lactone obtained above is filtered, dissolved in acetone, through 3 g of iron-free activated carbon, known under the trade name "Norit", and the eluate is evaporated in vacuo. 760 mg of a mixture with a melting point of 177 ° to 203 ° crystallize from acetone-ether ^{and is acetylated overnight with 10 cm 3 of} pyridine and 5 cm ^{3 of} acetic anhydride. It is then evaporated in a high vacuum at a bath temperature of 50 °, the residue is dissolved in 5 cm ^{3 of} benzene and chromatographed on 50 g of silica gel. With a benzene / ethyl acetate 4: 1 mixture, a small amount of a compound with a melting point of 222 to 227 ° is isolated after redissolving from benzene ether, which shows the following IR spectrum (solvent: CH ₂ Cl ₂ ): 5.63 µ (γ-lactone); 5.77 and 8.12 µ (acetate) and 9.10 µ (ketal). It should be one of the two isomeric 18,11-lactones in the 16-position

d, l - A ^{5 '14} - 3 - ethylenedioxy -1 iß - hydroxy -16 - acetoxyandrostadiene-18-acids are present.

The later benzene-ethyl acetate 4: 1 eluates consist, according to the IR spectrum, mainly of the cyclic hemiacetal acetate of d, l-z4 ⁵ > ¹⁴ -3-ethylenedioxy-II /? - hydroxy-lo.lS-dioxo-androstadiene, while finally further amounts of the 16-keto-lactone described above are eluted.

A solution of 239 mg of the <d ¹⁴ -16-keto-lactone described above in 150 cm ^{3 of} fine spirits is mixed with 300 mg of 10% palladium-carbon catalyst at normal

13 14

Painting pressure and room temperature in a hydrogen chloride are added with stirring 210 mg of d ^ l-Zl ^ -y

atmosphere stirred. In ^{1 and} ₂ hours, 1 mol equivalent of lendioxy-II / S-acetoxy-lojlS-dioxo-androstadiene becomes. To

Hydrogen added. Then it is sucked off, the 4-day stirring has dissolved everything, whereupon = on

Washed filter residue with methylene chloride and poured the dilute sodium bicarbonate solution and

The filtrate was evaporated to dryness in a water jet vacuum. 5 is extracted twice with benzene. The backlog of the

A crystallized residue (219 mg), washed with saturated sodium chloride solution and dried out, is obtained the organic which is recrystallized from methylene chloride and evaporated in vacuo

Ether 200 mg of the 18,11-lactone of the d, l-ü ^s -3-ethylene solutions are chromatographed on 7 g of aluminum

dioxy-ll /? - hydroxy-16-oxo-androstene-18-acid from the oxide (activity II). Located in the benzene fractions

Mp. 263 to 268 ° (in vacuo) can be obtained. io the d, l- / I ⁵ . ¹⁴ -3,18-diethylenedioxy-II / 3-acetoxy-

IR spectrum in CH ₂ Cl ₂ : bands at 5.65 μ (γ-lactone); 16-oxo-androstadien, after being dissolved twice

5.71 µ (16-CO); 9.14 µ (ketal). The further conversion from acetone-ether with the addition of 1 drop of pyridine

takes place according to the information of the German Auslegeschrift at 250 to 253.5 ° melts. S _{233 m / 1} = 14250.

1,061,779. IR spectrum in CH ₂ Cl ₂ : 5.77 and 8.12 µ (acetate);

Example 6 ¹⁵ 5.84 and 5.90 and 6.21 µ (J ¹⁴ -16-ketone) and broad band

^P between 9.03 and 9.22 μ (ketals).

To a solution of 200.4 mgd, 1-Zl ⁵ > ¹⁸ -3-ethylenedioxy-. .

Ilß, 18a-oxido-16-oxo48a-methyl-18-hoino-androstadiene Example 8

in 10 cm ^{8 of} absolute tetrahydrofuran and 0.115 cm ^{3 of} pyr- To a mixture of 30 cm ^{3 of} freshly distilled idin, a solution of 150 mg of 20 ethylenedithiol and 15 cm ^{3 of} absolute benzene is added while stirring, osmium tetroxide in 8 cm ^{3 of} ether is added, followed by 40 minutes a solution of 0.345 cm ^{3 of} pyridine in 15 cm ^{3 of} absolute precipitation occurs. After 20 hours of standing methanol and 15 cm ^{3 of} methanolic hydrochloric acid, at room temperature, 60 cm ^{3 of} methanol are added from 0.3 cm ^{3 of} acetyl chloride and 15 cm ^{3 of} methanol, diluted with a solution of 2 g of ammonia, while stirring stirring 3.08 g of d, LJ ^5-14 -3-Äthylenniumsulfit in 60 cm ³ of water are added, I ¹ Z ₂ hours 25 overall dioxy-LLSs-acetoxy-lo ^ S-dioxo-androstadiens added, stirred, by " Celite nitrated and with 150 cm ^{3 of} methanol. After everything has dissolved, it is rewashed for 12 days. The filtrate, which has largely been concentrated in a closed vessel at room temperature at a bath temperature of 40 to 50 °, is left with a water jet vacuum. It is then diluted with benzene, extracted, diluted with saturated sodium chloride solution and extracted twice with 150 cm ³ and seven times with 100 cm ^3, once with 30 cm ^{3 of} chloroform and three times with 30 5% aqueous ammonia and then twice more with chloroform-alcohol 7: 3 mix. The organic Lö- water, whereupon the aqueous solutions again with solutions are then shaken out individually once with 30 cm ³ 200 cm ^{3 of} ether. The residue is washed with half-saturated sodium chloride solution, combined, dried and evaporated organic solution, dried and evaporated in vacuo. Thereupon, one is freed from high-boiling components at 60 ° to dissolve the crystalline residue in 4.8 cm ^{3 of} 35 in a high vacuum. ^{Subsequently, 0.74 cm 3 is} dissolved in 10 cm ^{3 of} benzene methanol and 0.74 cm ^{3 of} pyridine with stirring and 90 g of aluminum oxide (activity II) of chromium 0.88N periodic acid solution. I ¹ Z ₂ hours later is matographed. Are obtained from the Benzoleluaten through with water and saturated saline solution diluted reprecipitation from acetone-ether 1.86 g of d, LJ ^{5 '14} -3-Äthy- and extracted three times with chloroform. The back dioxy-lo-ethylenedimercapto-ll ^ -acetoxy-IS-oxo level of the 30 cm ³ half-saturated saline solution 40 androstadiens from the mp 223 to 225.5 °. Washed in the IR spectrum, dried and evaporated in vacuo (solvent: CH ₂ Cl ₂ ) is only ten chloroform solutions in the carbonyl region, a solution of an intense band at 5.76 μ (aldehyde + acetate) of 400 mg of potassium carbonate in 12 cm ^{3 of} water and visible.

24 cm ⁸ alcohol. After boiling in nitrogen for 1 hour, a stream melted under vacuum in an ampoule, the cooled solution is poured onto a half-saturated mixture of 410 mg of the 11/3 saline solution described above and once with chloroform acetoxythio-ketal, 35 cm ^{3 of} methanol and 320 mg of potassium - and three times with a chloroform-alcohol-7: 3 mixture carbonate in 10 cm ^{3 of} water is shaken out while immersing in a. The residue is washed with a semi-saturated boiling methanol bath and using a magnetic saline solution, dried and stirred in the stirrer for 22 hours. After 12 hours, all organic extracts evaporated in vacuo are added, 50 dissolved. It is now slowly dissolved in 3 cm ^{3 of} pyridine to room temperature, allowed to cool with stirring and ice-cooling and then in an ice-common salt mixture to 100 mg of chromium trioxide in 3 cm ^{3 of} pyridine. After 3 hours. After filtering off, washing with ice-cold digem stirring at room temperature, dilute 70 ° / ₀ % methanol, water, 70 ° / ₀ % methanol and saline solution and benzene are added, the mixture is shaken well, ether gives 300 mg of the 18,11-cyclohemiacetal by » celite 'filtered, washed with benzene and 55 of the d, LJ ^{5' 14} -3-ethylenedioxy-ll / - re-extracted hydroxy-16-äthylendiwäßrige phase of the filtrate with benzene?. mercapto-18-oxo-androstadiens from melting point 220 to 221 °. The organic solutions are then shaken out. The IR spectrum shows a band at 2.79 μ (hydroxyl) twice with dilute sodium chloride solution and no band in chromium and in the carbonyl region,
matographed the residue of the dried and a cyclohemiacetal (activity II) produced from 260 mg of this cyclohemiacetal, 4 cm ^{3 of} pyridine vaporized benzene solutions in 3 g of aluminum oxide 60 and 4 cm ^{3 of acetic anhydride.} In the first benzene eluates there is acetate which, after dissolving from benzene-ether, melts in the 18,11-lactone of d, lJ ^s -3-ethylenedioxy-II /? - hy-198 to 200 °.

droxy-16-oxo-androstene-18-acid, which, after subliming, the IR spectrum in CH ₂ Cl ₂ : 5.75 and 8.15 μ (acetate);

at 200 ° in a high vacuum and dissolving from methylene 9.16 μ (ketal).

chloride ether melts at 263 to 268 °. It is with the 65 to a mixture of 1.25 g of the above cyclohemi-

compound described in Example 5 is identical. acetal acetate, 30 cm ³ acetone, 3 cm ³ water and 1.95 g

. -I ₇ mercury dioxide is added with stirring within 1 ^ hours

Example 7 _a solution of 2.2 g of mercury chloride in 9.5 cm ^{3 of} acetone.

To 20 cm ³ distilled over lithium aluminum hydride After stirring for 18 hours at room temperature,

Methylethyl-dioxolane and 20 mg of anhydrous ferric- 70 filter through "Celite" and rewash with 750 cm ³

15 16

Acetone is washed in vacuo at a bath temperature of 30 ° and evaporated from the filtrate under reduced small volume. The organic chloroform solution is then diluted with pressure at a bath temperature of 35 °, extracted twice with 40% strength potassium agent and removed as completely as possible. The precipitate iodide solution, three times with water and shaken, which is suctioned off, washed well with water and aqueous solutions in vacuo again with chloroform. 5 dried over phosphorus pentoxide. 7.27 g are obtained. The residue of the dried and evaporated crude d, l- / d ^B -3-ethylenedioxy-II / S, 18a; 14,15-dioxido-16-organic solutions are chromatographed on 50 g of oxo-IS. lSa-dihydroxy-lSa-methyl-lS-homo-androsten silica gel. In the benzene-ethyl acetate 3: 1 eluates with a melting point of 174 ° to 178 °. For the following period there is the d, l- /! The washed, moist crude 16-oxo-18-acetoxy-androstadiene can also ^{cleave 5il4 -3-ethylenedioxy-II / 3,18-oxido-acid cleavage.} In io product is used for cleaning. Dissolved from methylene chloride — methanol, treated with 200 mg of activated charcoal, recrystallized in methanol, the compound melts when nitrated, washed with methanol, concentrated and at 184 ° to 187 °. Allowed to crystallize when etched with molar amounts of osmium. 400 mg of the pure tetroxide can occasionally have a melting point of 200 to 202 °. Compounds with a melting point of 209 to 210.5 °. to be observed. The IR spectra of the two forms

. . _ 15 are identical.

Example y IR spectrum in Nujol: bands at 2.89 μ (OH);

10 g of the d, l- ^ ⁵ . ^{14th 18} -3-ethylenedioxy-II / ?, 18a-oxido-5.71 µ (16-CO) and 9.15 µ (ketal).

Lö-oxo-ISa-methyl-IS-homo-androstatrien are obtained in the same connection as follows

Dissolve 150 cm ^{3 of} benzene with gentle warming:

then mixed with 600 cm ^{3 of} methanol and cooled to 0 °. 20 4.82gd, l- <d ⁵ > ¹⁸ -3-ethylenedioxy-II / 3.18a; 14,15-dioxido-To the resulting clear solution are added 20cm ³ lo-oxo-lSa-methyl-lS-homo- androstadien are dissolved in ice-cold 4 η sodium hydroxide solution, stir well, and 100 cm ^{3 of} tetrahydrofuran are dissolved and cooled in ice. 45 cm ³ of about 30 ° / ₀ strength aqueous hydrogen peroxide to. The reaction mixture remains for 24 hours at 0 to 5 °, a solution of 3.18 g of osmium tetroxide in 100 cm ³ , with about 2.5 g of sodium hydroxide (NaHO ₂ ) 25 ether being added dropwise and the mixture 24 hours in coarse crystals separates. Then add to the room temperature. Then there are added vigorously stirred solution in small portions 2.0 g of 600 cm ³ of methanol, followed by a solution of 25 g of 2% palladium-calcium carbonate catalyst and ammonium sulfite in 600 cn ³ of water, and läßt2 _^3/4 hour stirring so long until no more oxygen escapes and do not stir at room temperature. The mixture becomes more detectable by hydrogen peroxide. As soon as this is sucked off a sintered glass funnel, the filter residue is the case, is sucked off and the filter residue is ^{washed with 200 cm 3 of} methanol and the cloudy filtrate is washed with methylene chloride. The colorless filtrate under reduced pressure to about 500 cm ³ is mixed with 40 cm ^{3 of} 2 η-acetic acid and then evaporated with stirring. It is then concentrated several times as much as possible with reduced pressure under reduced pressure (160 to form alcohol 7: 3 mixture extracted and the extracts 100 cm ³ ). Already during evaporation, 35 separates, washed with saturated sodium chloride solution. From the evaporated epoxy in crystallized form. Completed, dried extracts are obtained when the precipitation is complete, 1 liter of water is added and the steaming 4.01 g of crude, crystallized ^{d, 1A B} -3-ethylene mixture is left to stand overnight at 0 to 5 °. Then dioxy-II / JjlSa ^ .lS-dioxido-Lö-oxo-lS.lSa-dihydroxy the crystals are sucked off, washed well with water 18a-methyl ~ 18-homo ~ and rust. One made from methylene and then dried in vacuo over phosphorus pentoxide. 40 sample recrystallized with chloride melts at 200 to 202 °. Yield: 9.0 g d, l ^ ^5-18 -3-ethylenedioxy-LLSs, 18a; 14.15-7.27 g of the above-described crude 18,18a-diol dioxido-16-oxo-18a-methyl-18-homo-androstadiene vom are in a solution of 180 cm ^{3 of} dioxane and 3 cm ^{3 of} melting point 182 bis 196 °. This product is suspended in pyridine for the treatment and is ^{sufficiently pure with 30 cm 3 of} a M. periodic acid with osmium tetroxide periodate. One spiked out of solution. Then for 8 hours with room methanol and benzene-hexane recrystallized sample 45 is stirred at temperature, then with 350 cm ^{3 of} methylene epoxide melts at 199 to 201 °. chloride and twice with 220 cm ^{3 of} water each time

IR spectrum in CH ₂ Cl ₂ : bands at 5.72 μ (16-CO); washed. After shaking out the aqueous

5.96 µ (enol ether) and 9.16 µ (ketal). Solutions with 220 cm ^{3 of} methylene chloride and drying

380 mg of the above ketal epoxide in 6.4 cm ^{3 of} glacial acetic acid of the combined methylene chloride solutions are evaporated

and 5 cm ^{3 of} water are in a stream of nitrogen for 50 in a vacuum. From the raw product can through

Immersed in a bath of 100 ° for 15 minutes. Then crystallization from methylene chloride evaporates - ether 6.94 g ά, Ι-Δ ⁵ -

one in a vacuum, mixed with benzene, evaporated again S-ethylenedioxy-lljS-acetoxy-W.lS-oxido-lo.lS-dioxo-

in a vacuum and dissolves the residue several times from androsten from melting point 188 to 189 °. the

Benzene-ether-petroleum ether mixture around. The mother liquor obtained gives a further 0.36 g of something impure

d, l-zl * .i8-3,16-Dioxo-II | S, 18a; 14,15-dioxido-18a-methyl-55 product.

18-homo-androstadien melts at 226 to 233 °. Cha example 10
characteristic bands of the IR spectrum (solvent:

CH ₂ Cl ₂ ): 5.72 µ (5-ring CO); 5.98 μ (3-CO + dihydro- 3.0 gd, l- <d ⁵ > ¹⁸ -3-ethylenedioxy-ll / S, 18a; 14,15-dioxido-

pyran) and 6.17 μ (, ^ - double bond). Lö-oxo-ISa-methyl-IS-homo-androstadienjgelöstin10cm ³

To a solution of 7.00 gd, ^{1-4 5} > ¹⁸ -3-ethylenedioxy-60 dry pyridine and 60 cm ^{3 of} chloroform, at 11jS.lSajW.lS-dioxido-lo-oxo-ISa-methyl-IS-homo -andro- -17 ° for 26.5 minutes with a stage in 350 cm ^{3 of} tetrahydrofuran, an ozonated oxygen stream of 16.3 mg of ozone is first given a solution of 7.88 g of sodium periodate while stirring. The ozonide reduction and the uptake in 70 cm ^{3 of} water, then 7.88 g of crystalline. Sodium acetate and work in the manner described in Example 2, finally 70 mg osmium tetroxide. The tea-colored 65 with 10 cm ^{3 of} glacial acetic acid, 10 cm ^{3 of} water, 20 cm ^{3 of} pyridine and a mixture containing undissolved sodium acetate, about 10 g of zinc dust. The crude product is stirred in benzene for 24 hours at room temperature, 60 g of aluminum oxide (activity II) are chromatographed, and after a short time a white, fluffy low-temperature precipitate separates out of the middle benzene eluates 320 mg of ά, Ι-Δ ⁵ . After the reaction time has elapsed, 3-ethylenedioxy-IIJS-acetoxy-14,15-oxido-16,18-dioxo is suctioned off, and the filter residue is rusty and rusty with methylene chloride 70 and has a melting point of 176 ° to 181 °. By

17 18

Dissolving from benzene-ether, the melting point rises to the crude product triturated with ether, with the pure acetate

188 to 189 °. (2.214 g) remains undissolved. M.p. 245 to 253 °.

IR spectrum in CH ₂ Cl ₂ : bands at 3.70 μ (aldehyde); The crystallized from methylene chloride-methanol in prisms

5.72 μιιηά5.76 μ ^ ο-ΟΟ, ΑΜβΙιγα-Ι-ΕβΐβΓ-); 8.17 μ (Ac- callizing pure acetate changes from 220 ° to long

tat) and 9.13 µ (ketal). 5 needles around, which then melt at 249 to 252 °.

. . IR spectrum in CH ₂ Cl ₂ : bands at 5.70 µ with shoulder

Example 11 _at ^ _{73 μ (ester} _ _{and 16} _ _c0 ). _{813 µ} ( _Ace tat) and 9.15 µ

11.24 gd, 1-Zl ^{5 '18} -3-ethylenedioxy-II / S, 18a; 14,15-diox- (ketal).

ido-16-0X0-18 a-methyl-18-homo-androstadiene, dissolved in To a solution of 200 mg of the 18,11-cyclohemi-

a mixture of 340 cm ^{3 of} dioxane, 4.7 cm ^{3 of} pyridine 10 acetals des d, l-zl ⁵ -3-ethylenedioxy-ll _J i? -hydroxy-14,15- and 70 cm ^{3 of} water, are first with stirring oxido-16,18-dioxo-androstens in 9 cm ^{3 of} benzene and 1 cm ^{3 of} 75 mg of osmium tetroxide, then with 6.0 g of sodium periodate pyridine are added 0.2 cm ³ while stirring and cooling with ice. After stirring for half an hour at room temperature, freshly distilled benzoyl chloride. After 2 hours, 75 mg of osmium tetroxide and 4.5 g of sodium are again removed from the ice cooling and left to stand overnight at periodate and, after a further 5 hours, another 75 mg at room temperature. Then it is poured onto osmium tetroxide and 3.0 g of sodium periodate are added. Benzene and water and extracted twice with 0.1 N Na-Finally, the mixture is stirred for a further 9 hours and the trium hydrogen carbonate solution and three times with water, mixture is poured ^{into 500 cm 3 of water.} It is extracted, whereupon the aqueous solutions are extracted twice with fresh, then once with 500 cm ³ , then twice with 350 cm ^{3 of} benzene each time. After drying and methylene chloride, the extracts are washed twice each time. Evaporation of the organic solutions each time with 350 cm ^{3 of} water. The combined residue and the residue are redissolved several times from methylene chloride-acetone-dried methylene chloride extracts after an ether mixture. The thus obtained cyclohemid evaporation 14.22 g of an acetal benzoate which crystallizes with ether melts at 258.5 to 264.5 ° and shows in the residue. This is in a mixture of the same IR spectrum, the following characteristic bands: 5.69 μ parts by volume of benzene and hexane dissolved and 225 g of 25 (5-ring CO); 5.78 µ (benzoate) and 9.15 µ (ketal).
Chromatographed aluminum oxide (activity II). With . .

A total of 5.41 benzene-hexane 1: 1 mixture is isolated in Example 10

4.278 g of starting material, which after recrystallization 1.538 gd, l- ^ ⁵ -3-ethylenedioxy-II / ?, 18; 14,15-dioxido-

from methylene chloride-methanol melts at 201 to 203 °. 16-oxo-18-acetoxy-androstene in the presence of with 900 cm ³ of benzene 876 mg of a / ₀ palladium-calcium carbonate catalyst eluted product non-uniform 30 1.0 g of 10 °, while from 1.81 in Essigester 240 cm ^{3 of} fine spirits stirred under hydrogen. After eluted fractions by trituration of the evaporation the amount of hydrogen residue calculated for 1 mol equivalent with ether 5.834 g of a product at 173 to 181 ° has been taken up (after 9 hours), the hydrogenation melting product can be isolated, which interrupted the catalyst by filtration separated according to the IR spectrum and paper chromatography 35 and washed with methylene chloride. After analysis as almost pure d, l- / d ⁵ -3-ethylenedioxy-II /? -Acet evaporation of the filtrate in vacuo, 1.551 g of oxy-14,15-oxido-16,18-dioxo-androstene are obtained. one easily crystallized from methylene chloride ether

_. . , "Bable product. The raw product can be sent directly to the water

. ₇ Eispie cleavage can be used.

1.0 gd, l- / l ⁵ -3-Ethylenedioxy-ll ^ -acetoxy-14,15-oxido- 40 One more twice from methylene chloride-ether around -16-, 18-dioxo-androsten be crystallized in a mixture of Sample of d, l- / d ⁵ -3-ethylenedioxy-II / ?, 18-10 cm ³ abs. Methanol and 10 cm ³ abs. Tetrahydrofuran oxido-14-hydroxy-16-oxo-18-acetoxy-androstene melts suspended, cooled to 0 ° and with 4.8 cm ³ a temperature of 201.5 to 203.5 °.

0.5 n-sodium methylate solution in abs. Methanol added. IR spectrum in CH ₂ Cl ₂ : bands at 2.77 μ and 2.87 μ

The mixture is then stirred until a clear solution is obtained (approx. 45 (OH free and assoc.); 5.73 μ (Ester-CO and 16-CO) and 15 minutes), and this is 50 to 60 hours at 0 to 5 ° 8.13 μ (acetate).

left to stand under exclusion of moisture. Then 300 mg of the cyclohemiacetal acetate described above

0.5 cm ^{3 of} glacial acetic acid and 0.5 cm ^{3 of} pyridine are added and the solution is heated to 100 ° for 25 minutes in a mixture of 7.5 cm ^{3 of} glacial acetic acid and concentrated under reduced 7.5 cm ^{3 of water.} Then pressure is applied to about 5 cm ³ . This solution is then cooled with water 50, ^{poured into 75 cm 3 of} water and diluted, extracted twice with methylene chloride and ^{the extracts are washed three times with 100 cm 3 of} chloroform-alcohol 2: 1 mixture each time. The extracted. The extracts are left with sodium hydrogen-purified methylene chloride extracts in the monocarbonate solution and then 1.08 g of a crystallized residue evaporate with saturated sodium chloride solution. Shaken through, dried and evaporated in vacuo. Recrystallization from methylene chloride — ether can be obtained after drying and evaporation a total of 638 mg of 18,11-cyclohemiacetal of the crystallized residue (300 mg), from which, by crystallide, ⁵ -3-ethylenedioxy-II /? - hydroxy -14,15-oxido-16,18-sation from methylene chloride-methanol, a first fraction of dioxo-androstene with a melting point of 243 to 248 ° is obtained from 188 mg of the cyclohemiacetal of d, l-Zl ⁴ -3,16,18 -be . A sample made from methylene chloride-methanolic crystalline trioxo-II / 3.14 _i -dihydroxy-androstene with a melting point of 239 melts at 251 to 254 °. 60 to 240 ° is obtained. Separates from the mother liquor

IR spectrum in CH ₂ Cl ₂ : bands at 2.79 μ (OH); another amount of somewhat more impure substance is deposited. The 5.70 μ (16-CO) and 9.15 μ (ketal). Compound stubbornly retains solvents; at the

To produce the acetate, it is advantageous to use drying at a higher temperature, it decomposes adheres the raw saponification product. 4.277 g of raw discoloration.

Soap product are in 30 cm ³ pyridine and 20 cm ³ 55 UV spectrum: maximum at 240 ηαμ (ε = 16150), acetic anhydride 48 hours at room temperature IR spectrum in Nujöl: bands at 2.96μ (OH); 5.77 μ left to stand, the acetate partially already in (16-CO); 5.98 µ and 6.18 µ (α, β-uns. Ketone).
Crystals are deposited. Then 2.51g of crude d, l-z4 ⁵ -3-ethylenedioxy-ll / ?, 18-oxido-14-

evaporated to dryness, the residue several times in hydroxy-lo-oxo-IS-acetoxy-androsten are dissolved in 480 cm ^{3 of} benzene and each time evaporated again and the 70 abs. Dissolved benzene and after adding 12.0 g of "neutral"

Aluminum oxide (Woelm, activity I) was refluxed for 2 hours with stirring and with exclusion of moisture at a bath temperature of 110 °. It is then cooled, the now red-colored aluminum oxide is filtered off with suction and washed thoroughly with methylene chloride. (G 2.22, absorbance at 232 ταμ .: 14300) from the residue obtained by evaporation of the Fütrats in vacuo may be prepared by crystallization from ether 1.63 g d, lA ^5-14 -3-ethylenedioxy-1 IJS , 18-oxido-l 6-oxo-l 8-acetoxy-androstadiene with a melting point of 209 to 210.5 can be obtained.

UV spectrum: e _{232 m} "= 16600. IR spectrum in CH _a Cl ₂ : bands at 5.75 μ (ester-CO); 5.84 μ with shoulder at 5.90 and 6.19 μ (J ¹⁴ -16 ketone); 8.18 µ (acetate) and 9.08 to 9.16 µ (ketal).

A further amount of something impure crystallizes from the mother liquor when it is concentrated and left to stand for a long time Product.

Example 14

22.0 mg of d, lJ ⁵ -3-ethylenedioxy-II / 3,18-oxido-14-hydroxy-lo-oxo-IS-acetoxy-androstene and 11.2 mg. Benzoic acid in 2.0 cm ³ abs. 0.08 cm ^{3 of} a solution of triethylamine in xylene (containing 1.0 cm ^{3 of} triethylamine in 10.0 cm ^{3 of} solution) are added to xylene and the mixture is refluxed for 12 hours under nitrogen at a bath temperature of 160 °. The mixture is then allowed to cool, diluted with benzene and washed with water, sodium hydrogen carbonate solution and water, and the aqueous solutions are each extracted twice with benzene. From the combined, dried benzene solutions, 28 mg of crude product are obtained, which shows an extinction of 11600 at 231 πΐμ. Crystallization from ether first yields 8.9 mg of crystals with a melting point of 207 to 209 °, which, after being recrystallized again from ether, melt at 217 to 220.5 °. Analysis and IR spectrum show that it is dl - ^ - S-ethylenedioxy-llß.l 16-oxo-18-benzoyloxy-androstene.

UV spectrum: e ^ i _mß = 12100. IR spectrum in CH ₂ Cl ₂ : bands at 2.77 and 2.86 µ (OH free and assoc.); 5.72 µ (16-CO); 5.79 µ (benzoate) and 9.12 µ (ketal).

A further 6.3 mg crystallize from the mother liquor from the first crystallization, which, according to the mixed melting point and IR spectrum, has the above-described d, lJ ⁵ ₁ ¹⁴ -3-ethylenedioxy-II _J 8,18-oxido-16-oxo-18- acetoxyandrostadiene proves to be identical.

Example 15

500 mg of pure d, l-.d ⁵ . ¹⁴ -3-ethylenedioxy-LLSs, 18-oxido-16-oxo-18-acetoxy-androstadien are hydrogenated in 150 cm ³ rectified spirit with 500 mg of 10% PaUadium-calcium carbonate catalyst at normal pressure and room temperature. The hydrogenation is interrupted after absorption of one molar equivalent of hydrogen (about 7 hours). The solution filtered off from the catalyst is evaporated, and the residue crystallizes completely on spraying with ether, melting point 212 ° to 226 °. The d, lA ⁵ -3-ethylenedioxy-1 Iß, 18-oxido-16-oxo-l 8-acetoxy-androstene recrystallized from methylene chloride ether slowly sublimes in small cubes from 220 ° and then melts at 243 to 246 °.

IR spectrum in CH ₂ Cl ₂ : bands at 5.74 μ (16-CO and ester); 8.18 µ (acetate) and 9.11 µ (ketal).

A solution of 410 mg of this acetate in 65 cm ^{3 of} methanol is mixed with a solution of 540 mg of potassium carbonate in 17.5 cm ^{3 of} water and left to stand for 20 hours at room temperature. Q, 22 cm ^{3 of} glacial acetic acid, 50 cm ^{3 of} water and 200 cm ^{3 of} saturated sodium chloride solution are then added, and the ^{mixture is extracted once with chloroform and three times with 70 cm 3 of a} chloroform-alcohol 7: 3 mixture. The residue of the dried and evaporated organic solutions is redissolved twice from methylene chloride-ether. The thus obtained d, lJ ⁵ -3-ethylenedioxy-II /? - hydroxy-lo ^ S-dioxo-androstene-cyclohemiacetal melts at 253 to 258 °. The IR spectrum (solvent: CH ₂ Cl ₂ ) shows the following characteristic bands: 2.78 μ (hydroxyl); 5.73 µ (5-ring CO) and 9.12 µ (ketal).

250 mg of the above-described d, l-Zl ⁵ -3-ethylenedioxy-1 iß - hydroxy -16.18 - dioxy - androstene - cyclohemiacetal are ^{dissolved in 6 cm 3 of} glacial acetic acid in the heat, then 6 cm ^{3 of} water are added and 30 Heated minutes to 100 ° while passing nitrogen over it. Then it is evaporated in vacuo and the last residues of glacial acetic acid and water are removed by adding benzene twice and evaporating in vacuo. After the residue has been redissolved several times from methanol — methylene chloride — ether, the cyclohemiacetal of d, l- ^ I ⁴ -3,16,18-trioxo-11/9-hydroxy-androstene melts at 242 to 246 °. Characteristic bands of the IR spectrum in Nujol: 2.85 μ (hydroxyl); 5.73 µ (5-ring CO) and 6.05 and 6.20 µ (Zl ⁴ -3-ketone). ^ε 24ο η /! - 16500.

To 100 mg of chromium trioxide in 3 cm ^{3 of} pyridine, while stirring and cooling with ice, 90 mg of the cyclohemiacetal of d, lJ ^s -3-ethylenedioxy-II / 3-hydroxy-16,18-dioxoandrostene are added. After 15 minutes, the ice cooling is removed, the mixture is stirred for a further 4 hours at room temperature and then benzene and semi-saturated sodium chloride solution are added. After filtering through "Celite", rewashing with benzene and re-extracting the aqueous phase of the filtrate twice with benzene, the benzene solutions are extracted three times with semi-saturated sodium chloride solution. The residue of the dried and evaporated organic solutions melts after repeated redissolving from acetone-ether and pure acetone at 259 to 266 ° and, with the 18,11-lactone described in Example 5, is the d, l-Zl ⁵ -3-ethylenedioxy-16 -oxo-1 lß-hydroxy-androsten-18-acid identical.

Example 16

150 mg of the free cyclohemiacetal of d, l-Zl ⁵ -3-ethylenedioxy-ll ^ -hydroxy-14,15-oxido-16,18-dioxo-androstens are, as indicated in Example 13 for the acetate, with 100 mg of palladium -Calcium carbonate catalyst (10%) ^{hydrogenated in 25 cm 3 of} fine spirits. Crystallization of the crude product from a methylene chloride-methanol-ether mixture gives 124 mg of d, l-Zl ⁵ -3-ethylenedioxy-11 / U4-dihydroxy-solution-lS-dioxo-androstene-cyclohemiacetal of melting point 247 to 249 ° ( Decomposition). IR spectrum in Nujol: bands at 2.88 and 2.94 μ (OH); 5.74 µ (16-CO) and 9.16 µ (ketal).

50 mg of this cyclohemiacetal are acetylated in 2 cm ^{3 of} pyridine and 1 cm ^{3 of} acetic anhydride overnight. Then with 10 cm ³ abs. Diluted benzene, admixed with 2.0 cm ^{3 of} methanol and worked up in the usual way after 2 hours. 40 mg of d, l-Zl ⁵ -3-ethylenedioxy-II / U8-oxido-14-hydroxy-16-oxo-18-acetoxy-androsten, which after Melting point, mixed melting point and IR spectrum with the compound described in Example 13 is identical.

Example 17

^{2 cm 3 of} acetyl chloride are added with stirring to a mixture of 200 cm ^{3 of} dry benzene, 2.3 cm ^{3 of} absolute pyridine and 2 cm ^{3 of absolute methanol.} 20 minutes later, 16 gd, 1-Zl ⁵ -3-ethylenedioxy-IIJS-hydroxy-W.lS-oxido-lo.lS-dioxo-androstene-cyclohemiacetal and 250 cm ^{3 of} dihydropyran are added. The mixture is now allowed to stir for 96 hours with exclusion of moisture at room temperature, then diluted with benzene and

extracted with dilute sodium hydrogen carbonate solution and three times with water. The aqueous solutions are shaken out twice with benzene, whereupon the combined and dried organic solutions are evaporated in vacuo at 50 °. After removing volatile components at 50 ° in a high vacuum, the solution of the residue in benzene is filtered through 80 g of aluminum oxide (activity II). The d, l-Zl ⁵ -3-ethylenedioxy-11ß, 18; 14,15-dioxido-16-oxo-18-tetrahydropyranyloxy-androstene is in the first 21 filtrate as a mixture of stereoisomers. The first crystallizate obtained from methylene chloride-ether is 15.24 g with a melting point of 193 ° to 201 ° (decomposition). The IR spectrum recorded in methylene chloride no longer shows any hydroxyl bands. In the carbonyl region only the five-membered ketone band is found at 5.7 μ.

10.21 g of the above-described d, l-Zl ⁶ -3-ethylenedioxy-11 / 3.18; ³ rectified spirit by addition of 5.0 g of 10 ° / ₀ palladium-calcium carbonate catalyst ao be anyloxyandrosten tetrahydropyr until the uptake of 1 molar equivalent of hydrogen shaken in 800 cm - 14,15 - dioxido -16 - -18 0x0. The catalyst is then separated off by filtration, washed with methylene chloride and the filtrate is evaporated to dryness in a water-jet vacuum. The resulting crude d, l-Zl ⁵ -3-ethylenedioxy-II / ?, 18-oxido-14-hydroxy-16-oxo-18-tetrahydropyranyloxy androstene can be used directly for the elimination of water described below. A sample of the pure 14-hydroxy compound recrystallized from methylene chloride ether melts at 184 ° to 186 °. IR spectrum in CH ₂ Cl ₂ : 2.78 and 2.85 µ (hydroxyl) and 5.73 µ (5-ring ketone).

10.30 g of the above crude 14-hydroxy compound are abs ^{in 1000 cm 3.} Dissolved benzene and stirred under reflux for 3 hours with 30 g of neutral aluminum oxide (activity I) in a nitrogen atmosphere. After cooling, the aluminum oxide is filtered off with suction, washed with 300 cm ^{3 of} benzene and the light yellow filtrate is evaporated to dryness in a water jet vacuum. By crystallizing the residue (9.4 g) from ether, a total of 8.23 pure d, lA ^{5 '14} -3-ethylenedioxy -1 Iß, 18-oxido -16-0X0-18-tetrahydropyranyloxyandrostadiene is isolated in two fractions. The compound recrystallized again from ether melts at 161 to 163 °. UV spectrum: maximum at 236 πιμ (ε = 16300). IR spectrum in CH ₂ Cl _2: 5.85 and 6.20 μ (4 ¹⁴ -16-ketone).

100 mg of the 18,11-hemiacetal of ά, Ι-Λ ^s -3-ethylenedioxyll ^ -hydroxy-14,15-oxido-16,18-dioxo-androstens ^{used as starting material in the above example, suspended in 20 cm 3 of} glacial acetic acid, are immersed in an oil bath at 100 °, and the clear solution is treated ^{with 1.0 cm 3 of water after 2 minutes.} After a further 5 minutes at 100 °, the mixture is poured into 30 cm ^{3 of} water, extracted several times with methylene chloride and the extracts are washed neutral with dilute sodium hydrogen carbonate solution. 84 mg of a crystallized residue are obtained from the combined, dried methylene chloride solutions. Recrystallized from methylene chloride ether, the pure 18,11-hemiacetal of d, lJ * -3,16,18-trioxo-II / 3-hydroxy-14,15-oxido-androstene melts at 244 to 246.5 ° (dec -Settlement). UV spectrum: maximum at 238 ηΐμ (ε = 15200). IR spectrum in Nujol: 2.98 µ (hydroxyl); 5.73 μ (5-Rüigketon) and 5.95 and 6.18 μ (Zl ⁴ -3-ketone).

^{In a completely analogous manner, the same hemiacetal of d, l-Zl 4} -3,16,18-trioxo-lβ-hydroxy-14,15- is obtained from the 18-tetrahydropyranyl ether and from the 18-acetate of the hemiacetal described in Example 16 oxidoandrosten from m.p. 244 to 246.5 °.

Example 18

100 mg dl-Zfs ^ -yy ^ 18-tetrahydropyranyloxy-androstadien are mixed with 25 cm ³ rectified spirit, and 10 mg of a 10 ° / ₀ by weight palladium-calcium carbonate catalyst in a hydrogen atmosphere until uptake of the saturation of the 14 (15) -double bond required amount of hydrogen stirred. The catalyst is then filtered off, washed with benzene and evaporated to dryness in vacuo. Recrystallized from methylene chloride ether, the ά, Ι-Λ ⁵ -3-ethylenedioxy-16-oxo-ll, 3,18-oxido-18-tetrahydropyranyloxy-androstene melts at 213 to 219 °. IR spectrum in CH ₂ Cl ₂ : 5.74 µ (5-membered ring ketone) and 9.12 µ (ketal).

75 mg of the hydrogenation product obtained above are heated in a nitrogen stream with 10 cm ³ of 50 ° / _o glacial acetic acid minutes at 100 °. Then it is evaporated in a vacuum, mixed with benzene, evaporated again and this operation is repeated again. After redissolving the residue from methanol-ether, the cyclohemiacetal of d, lJ ⁴ -3,16,18-trioxo-II / 3-hydroxyandrostene is obtained, which with the preparation described in Example 15 does not lower the melting point and has an identical IR- Having spectrum.

Claims (3)

PATENT CLAIMS: 1. A process for the preparation of 11,18-dioxigenated 16-oxo-androstane compounds, characterized in that one in a Δ ⁴ » ¹⁸ -3,16-dioxo- Iß, 18 aoxido-18a-methyl-18-homo-androstadiene the formula which in 14 (15) position another double bond may have, or oxidatively cleaves the 18,18a double bond in a corresponding 3-ketal and in the obtained ll ^ -acetoxy-18-oxo compound the 11 / S-acetoxy group is saponified under alkaline conditions, with Presence of a 14,15 double bond this or the 16-oxo group is temporarily protected by known methods and optionally the one formed Functionally modified 18,11-cyclohemiacetal group and, if desired, hydrogenated the 14,15 double bond in a known manner at any reaction stage will. 2. The method according to claim 1, characterized in that the 18,18a double bond with Sodium periodate cleaves in the presence of pyridine and catalytic amounts of osmium tetroxide. 3. The method according to claim 1, characterized in that the 18,18a double bond with Sodium periodate is hydroxylated in the presence of sodium acetate and catalytic amounts of osmium tetroxide. A priority document was displayed when the registration was announced. © 1 909 75 & / 550 2.60