DE1192193B - Process for the production of 6ß, 19 oxido steroids - Google Patents

Description

^ FEDERAL REPUBLIC OF GERMANY "DEUTSCHES ^ JJEn ^ PATENTAMT

EDITORIAL

Int. α .:

core C 07J

"Uh-

German class: 12 ο - 25 / M

Number: 1192193

File number: C24472IVb / 12o

Filing date: June 28, 1961

Opening day: May 6, 1965

The invention relates to a process for the preparation of 6 / S, 19-oxido steroids from 19-unsubstituted ones 6 / ff-hydroxy steroids that are no further have free hydroxyl groups. The oxido steroids obtained are important intermediate products for the production of pharmacologically valuable 19-norsteroids, e.g. B. of certain derivatives of 19-nortestosterone and 19-nor-progesterons. For example, the 19-nor-17 «-methyl-testosterone that 19-nor-17 "-ethinyl-testosterone and esters of 19-nortestosterone found therapeutic use.

These compounds were previously mainly due to the reduction of steroid compounds with an aromatic Ring A accessible, which in turn consists of unsaturated 3-keto-steroids by thermal elimination the angular C-19 methyl group and simultaneous Flavoring had to be made. According to the method of the present invention Easily accessible 6 / 5,19-oxido-steroids enable now the manufacture of 19-nor-steroids on extremely simple way, without the ring A first having to be flavored.

The process according to the invention consists in treating a 19-unsubstituted 6/5 hydroxy-steroid which contains no further free hydroxy group with a monovalent, positive iodine-containing compound in an inert organic solvent, expediently at elevated temperature, and if so desired, in a manner known per se, the obtained 6 / ?, 19-oxido-steroid, before or after hydrolysis of acyloxy groups present, esterification of existing hydroxyl groups and / or introduction of a lower alkyl, alkenyl or alkynyl radical in the 17 "position obtained o / J. ^ - oxido-n-oxo-androstane compound or a hydroxyl group in the 17 <x-position of a 6 / 9,19-oxido-20-oxo-pregnane compound obtained, oxidized and optionally reduced oxo groups present in a known manner , dehydrated existing hydroxyl groups and / or introduces an I ⁴ -3-oxo group.

As starting materials for the process of the invention appropriate 6 /? - hydroxy compounds are suitable the Androstan, Pregnan, Cholan, Cholestan, Stigmastan, Spirostan and Cardanolide series, which in the ring system, in particular in one or more of the positions 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 14, 15, 16, 17, 20 and 21 may have further substituents, such as free or functionally modified oxo groups, esterified or etherified hydroxyl groups, alkyl (e.g. B. methyl) groups and / or halogen atoms. Under functionally modified oxo groups are Coalized or in enol derivatives, e.g. B. enol ethers or processes for the preparation of 6 / J, 19-oxidosteroids

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative:

Dipl.-Ing. E. Splanemann, patent attorney,

Munich 2, Theatinerstr. 33/34

Named as inventor:

Dr. Albert Wettstein, Riehen;

Dr. Georg Anner,

Dr. Karl Heusler,

Dr. Jaroslav Kalvoda, Basel;

Dr. Helmut Ueberwasser, Riehen;

Dr. Jules Heer, Binningen (Switzerland)

Claimed priority:

Switzerland of July 15, 1960 (8133),

of October 28, 1960 (12107),
of December 23, 1960 (14 393),
dated April 5, 1961 (3989),
dated June 2, 1961 (6479),
from June 13th WPt (6895)

Enol esters, converted oxo groups. In addition, the starting materials can also have double bonds or have oxido groups, e.g. B. in 4.5, 9.11 or 16.17 position.

Particularly important starting materials are corresponding oss-hydroxy compounds ^ which have a ZM-S-oxo group or in the 3- and 5-position those substituents which enable the formation of a / 4 ⁴ -3-oxo group, such as 3 <x protected in the 3- and 5-positions , 5 ", 6 / Mnhydroxy compounds, e.g. B. cyclic 3,5 carbonates, sulfites, acetonides or benzal compounds, or 3-esterified or etherified Δ ⁴ -3,6 / 9-dihydroxy compounds or 3,5-cyclo-6y5-hydroxy steroids or in particular 3-esters and 3-ethers of 3,6 / 3-dihydroxy-5 * -halogenosteroids or ketals of 3-oxo-5'-halo-6 / S-hydroxy-steroids, which are formed by the addition of hypohalous acid the corresponding 5,6-unsaturated compounds can be obtained.

509 568/458

3 4

Specific starting materials are z. B. The following The reaction can in an analogous manner with iodine Compounds: Sje-acetoxy-o / S-hydroxy-cholestane, and silver acylates or iodine and mercury acylates, 3,17-Dioxo-6/5-hydroxy-5a- or 5 /? - androstane, the z. B. acetates, or from these reagents ent-3,5-carbonate or 3,5-sulfite of the 3a, 5tx, 6 /? - trihydroxy-standing complexes can be carried out. Particularly 20-oxo-pregnans, the 3,5-carbonate or 3,5-sulfite of the 5 suitable solvents are saturated, cyclic 3 £ x, 5A, 6 / J-trihydroxy-17-oxo-androstane or hydrocarbons, such as cyclohexane, methylcyclo-3a, 5 <x, 6/3-trihydroxy-17 /? -Acetoxy-androstane or the hexane, dimethylcyclohexane, but aromatic corresponding compounds in which the free matic hydrocarbons, such as benzene, or halo-oxo groups are ketalized, as well as S ^ -acetoxy-six-chlorogenated Hydrocarbons, such as carbon tetrachloride or S / i-acetoxy-six-bromo-ojS-hydroxy-cholestane, io substance, hexachlorobutadiene, or mixtures of these S / S-Acetoxy-Sa-chlorine or S / S-Acetoxy-Sa-bromine solvents are used. The one needed 6/3-hydroxy-spirostane, S / S-acetoxy-Sa-chlorine or reaction time depends on the temperature or on S / J-acetoxy-fia-bromo-o / J-hydroxy-n-oxo-androstane, the solvent used. At work 3 / 3,17 / 3-DIaCCtOXy-Sa-ChIOr- or 3 / 9,17 / J-Diacetoxy- with lead tetraacetate in boiling cyclohexane is the 5 <% - bromo-6 / S-hydroxy-androstane, 3 / 9.17 / 3-diacetoxy- »5 reaction usually after about 1.5 to 3 hours 5 "-chloro- or 3 / 9.17 /? - diacetoxy-5" -bromo-6 / £? -Hy- terminated.

Droxy-17 «-methyl-andTostan, Zl ⁴ -3,17-Dioxo-6/5-hy- Apolar solvents favor the process

droxy-androsten, Sje-acetoxy-Sa-chloro-ö / S-bydroxy- homolytic decay of 6-hypoiodites

16,17a-oxido-20-oxo-pregnane; the 17.20; 20.21-bis compared to the heterolytic decay, which to

methylenedioxy compound of S / S-acetoxy-Sa-chloro- ao 6-ketones would lead. Is used as a reagent

6 / ?, 17 ″, 21-trihydroxy-20-oxo-pregnans, 3 / 3.20 / 3-diacetic acid or its derivatives, in particular

oxy-six-chloro-ö / S-hydroxy-Sa-pregnan, 3j8-acetoxy-50> Acylhypojodite, these are beneficial all in one

chlor-e / S-hydroxy- ^ na-oxido-ZO-oxo-Sa-pregnan, larger excess used, as this one too

the 18,20-lactone the Sß-acetoxy-six-chloro-ö / ^ O / J-di- homolytic decomposition into carbon dioxide and alkyl

Hydroxy-5 "-pregnan-18-acid, S / S-acetoxy-Sa-chloro-iodide suffer. From the reaction of lead

6 / S-hydroxy-20-oxo-pregnane, 3ß, Πα-diacetoxy tetraacetate acetyl hypoiodite formed with iodine

Sa-cnlor-oß-hydroxy- ^ O-oxo-pregnan, 3 /? - Acetoxy- arise z. B. slightly methyl iodide and carbon

Sa-chlor-öjö-hydroxy-na-valerianoyloxy-iO-oxo-pre-dioxide.

gnan or Sß-acetoxy-Sa-chloro-o / tf-hydroxy-nix-meth- For the implementation according to the process one works

oxy-20-oxo-pregnane. 30 expediently at an elevated temperature, e.g. B. between

These 6/9-hydroxy 50 and 150 ° C. used as starting materials. The reaction can also be carried out by According to the invention, compounds are made by irradiating the reaction solution with visible and / valuable, positive iodine-containing compound or ultraviolet light can be accelerated. It is implemented. Such compounds are e.g. B. N-iodine often advantageous, the irradiated reaction solution still carboxamides and imides, e.g. B. N-iodoacetamide 35 to add excess iodine. Since the transition of the or N-iodosuccinimide and cyanide iodine. Particularly advantageous · 6-hypoiodite in 60.19 ether free of hydriodic acid The use of hypoiodous acid is liable, and even a small amount of iodine is sufficient if one their derivatives, e.g. B. of alkyl hypoiodites, such as in the presence of an oxidizing swords. Butyl hypoiodite. Alkyl hypojodites can be z. B. metal acylate works, with its HiUe from the iodine Heavy metal oxides such as mercury oxide and hydrochloric acid form the free iodine back again oxide or lead oxide, with iodine and alcohols. will.

Particularly good yields of 6 / 3,19-oxido-steroids.

but when using acyl hypojodites, tenen 6 / 3,19-epoxides, the oxygenated C-19-methyl-

which are advantageously further oxidized from heavy metal acylates, groups. This can e.g. B.

z. B. acetates, propionates, trifluoroacetates, benzo-45 done by the 6 / 3,19-epoxides with strong

aten, of metals of the I. and II. subgroup of oxidizing agents, z. B. with ruthenium tetroxide,

Periodic table, e.g. B. from silver and mercury or especially with derivatives of hexavalent chromium,

silver acylates, obtained with iodine. A cheap one like chromic acid or tert. Butyl chromate, in solution

Acylhypojodite production also consists of means, z. B. lower fatty acids such as acetic acid or

the reaction of iodine with lead tetraacylates, 50 being propionic acid, or in chlorinated hydrocarbons,

Lead diacylates and acyl hypojodites are formed. like carbon tetrachloride, especially at elevated levels

Monovalent, positive iodine is also present in the compounds. B. between 50 and 100 ⁰ C, treated,

genes of iodine with other halogens, d. H. in chloroiodine is obtained by introducing an oxo group in

or bromoiodine. It is often beneficial to use the 19-position lactones from 6/3 hydroxy-steroid 19-acids.

iodine reagent used, in particular the acyl hypo- 55 On the other hand, in the process

iodite, acyloxy groups present directly in the 6 / 3,19-epoxides in the manner described above,

Prepare reaction solution yourself. At output z. B. in the 3- and 17- or 20-position, hydrolyzed and

substances that contain double bonds is the resulting hydroxy compounds to 3-ketones,

Process-related use of iodine compounds 3,17-diketones or 3,20-diketones are oxidized,

inasmuch as this halogen cannot be found in these 3-ketones in a known manner

Attaches double bonds. by bromination and dehydrobromination one

The process can be introduced in this way, for example, through a 4 (5) double bond. The result that the starting material in a compared to J ⁴ -3-oxo group can be particularly easily

the oxidizing agent inert solvent, e.g. B. 5a-hydroxy or 5 "-halogeno-3-ketones by Alkalieinem Hydrocarbon, dissolved or suspended, lead or acid treatment. With the 3-oxotetraacetate, Iodine and a weak base, e.g. B. Calcium- 5 «-halogen-6 / 5,19-oxido-steroids is sufficient for the Halocarbonat, adds and the reaction mixture with elimination of hydrogen already the mild treatment

Stirring heated under normal or elevated pressure. with alkali metal acetates or with pyridine.

5 6

It is ζ. B. also possible according to the method according to the method according to the above compounds

obtained 5 <x-halogen-6 / J, 19-oxido-17-oxo-androstane corresponding 3-oxo-5 λ-halogen-androstane and

obtained with lower alkyl, alkenyl or alkynyl metal esters thereof. Very important ones

connections, e.g. B. with methyl magnesium iodide, process products are the <d ⁴ -3-Oxo-6 / 8,19-oxido-

Methyllithium, ethylmagnesium iodide, isobutyllitbi- 5 compounds of the androstane series, namely z. B. that

um, allylmagnesium bromide, methallylmagnesiumzJ ⁴ -3,17-dioxo-6 / ö, 19-oxido-androstene, the zl ⁴ -3-oxo-

bromide, sodium, potassium or lithium acetylide, 6j8,19-oxido-17/3-hydroxy-androstene and its esters,

Propargylmagnesium bromide or lithium-methyl- J ⁴ -3-oxo-6 / 9,19-oxido-17/3-hydroxy-17Ä-alkyl-, -17 <* - al -

acetylid to implement. This gives (without the kenyl- and -17 <x -alkynyl-androstenes, especially the

5 "halogen group is attacked) the corresponding 17a-methyl, 17a-ethyl and 17" -AUyl compounds

the n ^ -hydroxy-Ha-alkyl-, -alkenyl- or -alkynyl- and esters thereof.

androstane. Subsequent to the reaction with which can be produced by the process of the invention

Organometallic compounds mentioned can, as above, also 3-hydroxy-5'-halogen-6 / ?, 19-oxido-pregnane

indicated, a / l ⁴ -3-oxo grouping are formed, and esters thereof, for example those in the 20-position

The / J ⁴ -3,17-Dioxo-6 | 9,19-oxido-andro-15 obtained have a free or esterified hydroxyl group or a

stene can be in free or ketalized oxo groups by known methods, in particular

Δ ⁴ -3-Oxo-17 ^ -hydroxy-6jö, 19-oxido-androstene above 3jff, 20-dihydroxy-5 "-chlor-6 ^, 19-oxido-pregnane

lead, e.g. B. by selective reduction with one and its ester, 3 ^ -Hydroxy-5 «-chlor-6 ^, 19-oxido-

complex metal hydride, e.g. B. with sodium borohydride, 20-oxo-pregnane and its esters, 3 /? - Hydroxy-5 «-chlor-

or by reducing both oxo groups, e.g. B. with ao 6 / 3.19; 16.17 <x-bis-oxido-20-oxo-pregnan and his

Lithium aluminum hydride, for ^{I 4} -3,17-diol and ester, 3 / ?, 17 "-dihydroxy-5 * -chlor- and -5 <x-bromo-

Reoxidation in 3-position with manganese dioxide or 6ß, 19-oxido-20-oxo-pregnane and its esters. Except-

with acetone and aluminum isopropylate- or -tert.- which can correspond to the above compounds

butoxide at room temperature. The 6 / 9,19-oxy-speaking 3-oxo-5a-halo-pregnanes and esters obtained

do-testosterone can then be obtained by known methods of the same. Special meaning

which are esterified. but have the <d ⁴ -3-oxo-6 / ?, 19-oxido compounds of the

Likewise, in 6β, 19-oxido-20-oxo-pregnane series obtained, namely z. B. the zl ⁴ -3,20-Dioxo-

pregnanen according to known methods a 17 * -stän- 6 / 3,19-oxido-pregnen, / d ⁴ -3,20-dioxo-6 / 3,19-oxido-

end hydroxy group are introduced, in particular 17a-hydroxy-pregnen and its ester, the Δ * -3,2O-di-

z. B. by enol acetylation to d ¹⁷ ( ²⁰ ) -20 acetate, 30 oxo-6 / 3.19; 16.17 «-bisoxido-pregnen and the 18.20-Lac-

Peracid oxidation and hydrolysis to the 17 "-hydroxytone der / l ⁴ -3-Oxo-6 / S, 19-oxido-20/3-hydroxy-pregnen-

20-ketone. 18-acid.

The products obtained by the process of the invention are also considered to be special process products

6 / 3,19-Oxido-steroids belong to the "Androstan-, Pre- mentioned the 19,6 / J-Lactones of the 3 / S, 6/3-Dihydroxy-

Gnanic, cholanic acid, spirostanic, cardanolide or 35 5 «-chloro-spirostan-19-acid, the 3 / 3.6 / 3.17 / 3-tri

Cholestan range. They preferably contain a hydroxy-5'-chloro-androstane-19-acid and its

J ⁴ -3-oxo grouping or in the 3- and 5-positions such 3,) 7-diacylates, the "ißfiss-O'xhyatoxy-Sa-chiot-XlOxo-

Substituents that cause the formation of a Δ ⁴ -3-oxo androstanic acid and its 3-acylates, the 3 / 3,6 / 3,

enable grouping; In particular, they are 20 / S-trihydroxy-5a-chloro-pregnan-19-acid and theirs

3,5-Dihydroxy-steroids and derivatives thereof, 3-Hy- 40 3,20-diacylates and the 3 / 5,6 / 3,17 "-Trihydroxy-5Ä -chlor-

Droxy-5-halogen-steroids and corresponding ethers 20-oxo-pregnan-19-acid and its 3,17-diacylates.

and esters, J ⁴ -3-hydroxy-steroids and corresponding Tn according to the process used or obtained

Ether and ester. Furthermore, the acid residues mean in particular esters according to the process

of the invention lactones from öß-hydroxy-steroid- those from aliphatic, cycloaliphatic !!, aralipha-

19 acids obtained which have a I ⁴ -3-oxo grouping 45 tables and aromatic carboxylic acids with 1 to

or in the 3- and 5-positions such substituents contain 15 carbon atoms, e.g. B. a formate, acetate;

keep that the formation of a zl ⁴ -3-oxo grouping propionate, butyrate, trimethylacetate, oenanthate,

enable; in particular 6 / 9,19 lactones from capronate, decanoate, cyclopentylpropionate, valeria

3,5-dihydroxy steroids and derivatives thereof or nat-, benzoate, furoate, hexahydrobenzoate, phenyl

of 3-hydroxy-5-halogen steroids and corresponding 50 propionate, trifluoroacetate, ethyl or methyl carbon

the ethers and esters. natrest.

The 6 / 3,19-oxido-steroidal obtained according to the invention

Tenten products are especially saturated and ide can be found in the patent applications

unsaturated 6 / 3,19-oxido compounds of the spirostane, C 24474 IVb / 12o and C 24475 IVb / 12ο described,

Cholestane, Androstane and Pregnane series, e.g. B. 55 method not claimed here easily in 19-Nor-

Convert 3-hydroxy-5 "-halogen-6 / S, 19-oxido-spirostane or steroids. The procedure of the first patent

-cholestanes and esters thereof, e.g. B. the 3 / J-Acetoxy- registration consists in that one in a 5 "-Halo

5 «-chlor-6 / Ö, 19-oxido-spirostane or -cholestane, the gen-6 / e, 19-oxido-steroid, which continues in the 19-position

3-Oxo-5 «-cb) or-6 / 9,19-oxido-spirostane or -cholestane can carry a hydroxyl or oxo group (i.e.

and the z ( ⁴ -3-oxo-6 / ?, 19-oxido-spirostane or -chole- 60 hemiacetals of 19-oxo-6/3-hydroxy compounds or

stan; further 3-hydroxy-5'-halogen-6 / 3,19-oxido-andr o- 19,6 β- lactones of 6/3-hydroxy-19-acids), the

stane and esters of the same, e.g. B. the 3 / 3,17 / 3-dihydroxy- 6 / 3,19-oxido bridge opens reductively. In the received

5a-chloro- and -SA-bromo-o / ^ W-oxido-androstane and 19-oxygenated Δ ⁵ steroids can be the oxygenated

its ester, the 3/3-hydroxy-5 «-chloro and -5a-bromo-C-19-methyl group after the introduction of a Λ ⁴ -3-Οχο-

6ß, 19-oxido-17-0x0-androstane and its esters, 6s grouping are split off in a known manner.

S & n / S-Dihydroxy-Sa-chloro-ö & ^ - oxido-na-alkyl- The reductive opening of the 6 / 3,19-oxido bridge takes place

or -alkenyl-, especially -Ha-methyl-, -Ha-ethyl- z. B. with an alkali metal in liquid ammonia

and -17 <x-allyl-androstane and its esters. Next or with 19.6 / Ö-Lactonen also with zinc and

7 8

Acetic acid. In the process of the second patent, for the production of the starting material

registration goes from Δ ⁴ -3-oxo-6ß, 19-oxido 5.00 g of cholesterol acetate dissolved in 65 ml of ether, with

steroids and treated them with reducing 8.0 g of chlorinated lime and 300 ml of water and that

average, e.g. B. with zinc and acetic acid. This creates reaction mixture after the addition of 6.1 ml of glacial acetic acid

J ⁵ -3-oxo-19-hydroxy compounds, which are easy, for example 5 to 30 minutes at 25 ° using a strong vibrator

mixed with acid to form I ⁴ -3-oxo-19-hydroxy compounds. After diluting with ether, the

stored and finally separated after oxidation of the 19-hyorganic layer, diluted with ice cold

hydroxyl group in a known manner in 19-nor-compounds - sodium hydrogen carbonate solution and water neutral-

gen can be transferred. washed, dried and evaporated in vacuo.

The following examples explain the invention. 5.65 g of a crystalline product are isolated,

proper procedures. The temperatures are in Celsius- this provides after recrystallization from ether-

degrees indicated. Petroleum ether 1.98 to 2.10 g des at 192 to 194 °

melting 3 β - acetoxy - 5 a - chlorine - 6 β - hydroxy -

Example 1 cholestans. This instructs in the IR spectrum

15 other absorption bands at 2.75, 5.78, 7.26,

a) To a suspension of 7.32, 8.05, 8.65, 9.70, 10.63 and 10.90 μ heated briefly to 80 °.

20.0 g calcium carbonate and 60.0 g pre-dried In the same way, from / l ^e -3 /? - acetoxy-17-oxo-

Lead tetraacetate in 21 cyclohexane is 16.0 g of iodine androstendasS ^ -Acetoxy-Six-chlor-öjÖ-hydroxy-n-oxo-

added and the reaction mixture in the dark androstane from F. 225 to 227 °, from zl ^e -3p \ 17 /? - Di-

Boiled under reflux for 30 minutes with stirring. After so acetoxy-androsten the S / J.njS-diacetoxy-Sa-chlor-

Addition of 10.0 g of 3 /? - acetoxy-5 <x-chloro-6 /? - hydroxy-6 /? - hydroxy-androstane with a temperature of 197 to 199 °

Cholestan is boiled for a further 3 hours under re-^ ⁵ -3 ^ -acetoxy-17 / J-hydroxy-17a-methyl-androstendas

river (in daylight). The slightly pink-colored solution 3ß- acetoxy-SÄ-chlor-o / S.nß-dihydroxy- 17 <x-methyl-

is then cooled, from inorganic androstane from F. 179 to 181 °, from J ⁶ -3 / ?, 17 /? - Di-

Salts filtered off, the residue exhaustively with 25 acetoxy- 17Ä-methyl-androsten das 3 / ?, 17 /? - diacetoxy-

Washed with absolute ether and the combined FiI-5Ä-chloro-6/9-hydroxy-17 <x-methyl-androstane and off

If the separating funnel would contain 10% sodium thio-diosgenin acetate, the S / J-acetoxy-six-chloro-ö / miydroxy-

sulfate solution and washed with water. The ones obtained with spirostan.

Sodium sulphate-dried solution gives after a b) To 3.60 g of crude 3 /? -Hydroxy-5 "-chlor-6 / ?, 19-oxide vaporizing in vacuo 11.20 g of a crystalline prodocholestane in 100 ml 8.00 g of chromium duct are added to pyridine. After recrystallization from ether-methanol trioxide in 150 ml of pyridine and the mixture is stirred, 8.95 g of 3β-acetoxy-5'-chloro-6/5, J 9-oxido-cho-cho-24 hours at 45 °. The cooled reaction mixture obtained lestane with a melting point of 139 to 140 °. The analytically pure is mixed with about 100 g of ice, added with UmVerbonn melts at 141 to 142 °; [m] d (c - 1.156; pivot slowly 100 ml of a 40 ⁰ / _o aqueous sodium CHCl ₃₎ = + 7.8 dz 1.0 °. 35 hydrogen sulfite solution and leaves for 15 minutes at 20 °

In the IR spectrum of the connection occur under stand. Then the green solution is using

Other absorption bands at: 5.78, 6.71, 8.06, ether extracted, the pyridine by washing out

9.05, 9.60, 10.55, 10.78, 11.65 and 12.50 µ. with dilute hydrochloric acid and water removed that

In the NMR spectrum (in carbon tetrachloride: re-drawn with sodium hydrogen carbonate solution and water on benzene) the band of the C-19 methyl ether layer is missing, dried and in the vacuum group at 314 Hz, on the other hand it is evaporated at 156 to 164 Hz. 2.690 g of crude ζ1 * -3-Οχο -a complex band that contains the C-19 or. C-6-CH ₂ - 6 / $, 19-oxido-cholcstan. Which can be attributed to O or CH-O protons by chromatography. non-crystallizing ones purified with aluminum oxide

Instead of cyclohexane, lead compound shows absorption bands in the IR spectrum for the oxidation

tetraacetate also benzene used as a solvent 45 among others at: 6.00, 6.85, 7.25, 8.35, 8.80, 9.80,

will. 10.40, 10.60 and 11.40 µ. Shows in the UV spectrum

4.00 g SjS-Acetoxy-Sa-chloro-ojS. ^ - oxido-cholestane they have an absorption maximum at 241 ιημ.
are dissolved in 500 ml of methanol in the heat and in an analogous manner from the 3/9 hydroxy with a warm solution of 4.00 g of potassium carbonate 5 * -chlor-6 |?, 19-oxido-spirostane is obtained in very good yield 25 ml of water are added. After 1 hour on the back 50 the zl ⁴ -3-Oxo-6jö, 19-oxido-spirosten. IR spectral flow is the reaction solution with the addition of the at 5.98, 6.80, 9.50, 9.83 and 10.20 μ.
Water in vacuo until the methanol _{R is} removed. . . .
concentrated and taken up in ether. The etheric ti e 1 s ρ 1 e ι
The solution is washed twice with water, dried with a) 22.0 g of calcium carbonate and 66.0 g of dried sodium sulfate and evaporated. It is 55 lead tetraacetate in 3.3 1 cyclohexane suspenin quantitative yield, the 3 /? - Hydroxy-5ix-chlorinated dated, heated to 80 ° and the mixture after addition of 6 / 3,19-oxido-cholestane with mp 136 bis 138 ° received. of 17.6 g of iodine while stirring in the dark for 20 minutes. After a single recrystallization from methanol, it is refluxed. The slightly cooled reaction compound had a mp of 137-138 °. 11.0 g of 3 / δ-acetoxy-IR spectrum are added to the tion solution, among other things, absorption 60 5ui ^ chlorine-6; δ-hydroxy-17-oxo-androstane and boil at 2.80, 6.73 , 9.55, 10.03, 10.60, 10.87, 11.05 closing with stirring in daylight for 2 hours on and 12.10 μ. Reflux. The cooled reaction mixture is

In an analogous manner, 5.0 g of 3 / S-acetoxy-filtered are obtained, the residue exhaustively with absolute

5L \ -chlor-6 /? - hydroxy-spirostane 4.4 g of 3/5-acetoxy ether washed out and the filtrate with 10%

5a-cblor-6 / 3,19-oxido-spirostane, which is washed as above 65 sodium thiosulphate solution and water. To

indicated for 3 /? - Hydroxy-5a-chloro-6 / ?, 19-oxido-spi- dem evaporation of the dried solution in vacuo

rust can saponify. IR spectral bands at 2.78, 12.1 g of a crystalline product are obtained.

6.74, 9.53, 9.85, 9.90, 10.21 and 10.40 µ. After recrystallization from ether, this gives

Methanol 7.65 g 3 /? - acetoxy-5'-chloro-6 / 5,19-oxido-17-oxo-androstane from 180 to 182 °. In the IR spectrum the pure connection occurs among other things absorption bands at 5.76, 6.73, 7.35, 8.10, 9.65, 10.60, 10.82, 11.35, 11.67 and 12.50 µ.

2.0 g S / J-Acctoxy-S ^ -chlor-ö / J. ^ - oxido-n-oxo-androstane are dissolved in 200 ml of methanol, with a solution of 2.0 g of potassium carbonate in 10 ml of water added and refluxed for 1 hour. The reaction mixture is with the addition of water in Freed from methanol in vacuo, taken up in ether, washed three times with water, with sodium sulfate dried and evaporated. 1.620 g of SSHdShlo ^ lPidnd are obtained

/ y /
with a temperature of 223 to 226 °. After recrystallization from methylene chloride-methanol, the pure compound melts at 227 to 229 ° and has, among other things, absorption bands at 2.80, 3.28, 5.78, 6.75, 9.55, 9.78, 10 in the IR spectrum , 05, 10.63, 10.87, 11.33, 11.70 and 12.55 µ.

b) To an oxidation mixture consisting of 3.00 g of chromium (VI) oxide and 60 ml of pyridine is added 1.500 g of S / J-hydroxy-Sx-chloro-o / f. ^ - oxido-n-oxo-androstane . After 24 hours at 45 to 50 ", the reaction mixture is cooled, 50 g of ice and 50 ml of 40% sodium hydrogen sulfite solution are added, the mixture is extracted with ether and worked up as described in Example 1, part b) single recrystallization from methylene chloride-methanol 825 mg Δ ^ -3,17-dioxo-6 #, 19-oxido-androstea with a melting point of 184 ° to 186 °. Among other things, absorption bands at 5.80, 6, 01, 6.82, 6.95, 7.35, 7.65, 8.40, 8.81, 9.23, 9.80, 9.92, 10.40, 10.63, 11.40 and 12, 30 μ on.

c) 7.5 g of 3/9-acetoxy-6 | 3,19-oxido-5'-chloro-17-oxoandrostane are treated in 100 ml of toluene with a Grignard reagent, which consists of 8 ml of methyl iodide in 120 ml of ether using excess magnesium. After the heat development has stopped is heated while distilling off the solvent until the temperature of the remaining Reaction mixture has risen to 90 °. Maa dilutes with benzene and brings the reaction products by adding aqueous ammonium chloride solution and dilute hydrochloric acid in solution. The organic phase is obtained by washing with sodium thiosulfate solution, drying and Concentrate 7 g of crude 3 / 5,17 ^ -dihydroxy-5'-chloro-6 / 3,19-oxido-17Ä-methyl-androstane, which crystallizes on addition of a little methylene chloride and from isopropanol is obtained in crystals with a melting point of 212 ° to 214 ° with one molar equivalent of crystalline isopropanol. Treating 9 g of this product in acetone solution with excess aqueous chromic acid in the presence from a little sulfuric acid for 10 minutes at 10 to 15 °, diluted with a lot of water, wins crude oxidation product by suction filtering and boiling the moist filter residue in 1 liter of methanol containing 25 g Potassium acetate with distilling off methanol is obtained after taking up in benzo), washing the benzene solution with water, drying and evaporation 6.9 g 6 / S, 19-Oxido-l7 «-methyl-testosterone, which, recrystallized from benzene, melts at 157 to 158 °.

By reacting the 3 / S-acetoxy-6 / 3,19-oxido-5a-chloro-17-oxo-androstane is obtained in an analogous manner with ethyl magnesium bromide the 3 / ?, 17 / S-dihydroxy-5 <x-chloro-6 / ?, 19-oxido-17. * - ethyl-androstane, which, as stated above, yields 17-x-ethyl-tcstosterone by oxidation and treatment with potassium acetate. IR spectral bands at 2.80, 5.98, 6.23, 6.80, 8.80, 9.75 and 11.35 µ.

In the above example, instead of methyl magnesium iodide, allyl magnesium bromide is used on, you first get the 3 / 9,17 /? - dihydroxy-5 "-chloro-6 / 3,19-oxido-17" -allyl-androstane, which as

ίο Crude crystals melt at 205 to 207 ° and in the infrared spectrum absorption bands at 2.75 / 6.12, 6.75, 6.90, 7.60, 9.50, 9.76, 10.00, 10.85, among others μ shows. From this, in the manner described above, using chromic acid, the 3-oxo-17 /? -Hydraxy-5'-chloro-6 / 3,19-oxido-17 (x-allyl-aadrostane (characteristic bands in the IR spectrum at 5, 80, 6.10, 6.70, 7.50, 8.10, 9.10 and 9.70 μ) and by subsequent treatment with methanolic potassium acetate, as indicated above, the A ^A -3-Ox.o-Gß , l9-O} ado-ni \ -Myl-

ao 17/5-hydroxy-androsten from F. 90 ° (characteristic Bands in the IR spectrum at 6.00, 6.10, 6.80, 7.26, 8.35, 8.75, 9.74, 10.63, 11.36 μ) were produced.

d) 5 g 3 /? - acetoxy-5a-chloro-6) 9,19-oxido-17-oxo-androstane, dissolved in 100 ml of glacial acetic acid, are at 85 to 90 ° in the course of 30 minutes with a solution of 7.5 g of chromium trioxide in 7.5 ml of water and 60 ml of glacial acetic acid are added. After a further 15 minutes reaction time it is diluted with water and extracted with methylene chloride. The methylene chloride solution is with Washed water, sodium hydrogen carbonate solution, then dried with sodium sulfate and evaporated. 2.2 g of 19.6 / J-lactone of S / i-acetoxy-SÄ-chloro-6 /? - hydroxy-17-oxo-androstane-19-acid are obtained, which crystallizes by adding ether and by dissolving from alcohol of still existing oxido compound is released. The pure lactone melts at 198 to 199 °.

The S / S-acetoxy-S obtained according to Example 1 can also be obtained in an analogous manner

spirostan to the lactone of the sweet

6 (Oxidize S-hydroxy-spirostan-19-acid. IR spectral bands at 5.68. 5.75, 8.38, 9.53, 9.90, 10.20 and 10.41 µ.

e) To a suspension of 16 g of lithium aluminum hydride in 1.5 1 of tetrahydrofuran, a solution of 40 g of z! ⁴ -3,17-Dioxo-6 / ?, 19-oxido-androstene in 800 ml of tetrahydrofuran. The mixture is then heated to boiling under reflux for 1/2 hours, cooled to 10 ° and a mixture of 500 ml of ethyl acetate in 1.5 liters of ether is allowed to run in at 10 ° to 20 °. At the same temperature, a solution of 300 g of sodium sulfate (anhydrous) in 900 ml of water is then added, the organic solution is decanted off and the remaining layer of sludge is stirred twice with methylene chloride. The methylene chloride solutions are washed with 500 nil 2 η hydrochloric acid and combined with the tetrahydrofuran solution. The dried, filtered solution is then evaporated under reduced pressure, first at 60 °, then at a bath temperature of 40 °. 40 g of crystalline J ^J -3,17i? -Dihydroxy-6 / ?, 19-oxido-androsten, which, redissolved from chloroform, melts at 227 to 229 °. The crude reduction product obtained (40 g) is dissolved in 300 ml of acetone and 1.21 of benzene and stirred in a nitrogen atmosphere after adding 80 g of aluminum isopropylate at 30 ° to 31 ° for 17 hours. 140 ml are added to the cooled reaction mixture

509 568/458

11 12

5O ° / _O strength rapidly Rochelle salt added dropwise. Man lamp with stirring further. After an hour is

the clear organic layer is decanted and the solution is stirred until colorless. It is cooled, filtered and washed with

the 'viscous aqueous part with 11 benzene. Cyclohexane and shakes the filtrate with mixed

The combined organic solutions are washed with a thin sodium thiosulphate solution. Then dry

Sodium sulfate dried and concentrated in vacuo, the organic solution is 5 and evaporated in

steams. The residue is dissolved in ether, a water jet vacuum. The oily residue (22.75 g)

a 7 cm high column with aluminum oxide (Durch- is dissolved in a Beiizol-hexane (1: 4) mixture and through

knife 4 cm) filtered and evaporated again. The 200 g of aluminum oxide is filtered. First a high-

provides crude product weighing about 40 g, ^{eluted from 60 cm 3 of} boiling oil, and with benzene-hexane (1: 4) and

Recrystallized acetone, a first fraction of 24 g of io - (1: 1) mixture, about 7.0 g of substance are eluted.

pure Zl ⁴ -3-Oxo-6 / J, 19-oxido-17 / J-hydroxy-androsten by crystallization of this fraction residue

(6 / ?, 19-oxido-testosterone) in acetone-containing crystals of methylene chloride-ether gives 5.5 g of the pure

from 78 to 80 °. After prolonged heating in high-S / J-acetoxy-sa-bromo-o / UP-oxido-n-oxo-androstane

vacuum melts the connection at 127 to 130 °. with the double F. 174 to 178/184 to 187 °; [tx] _D

I) J2.2 g of 6 / 3.19-oxido-testosterone are in 36 ml of 15 = H-44.6 (in chloroform); the connection shows im

Pyridine dissolved and at 10 to 15 ° with stirring within IR spectrum, among other things, bands at 5.76, 6.68,

half of 2 minutes with 8 ral capric acid chloride 7.30, 8.09, 9.16 and 10.92 μ.

puts. The reaction mixture is allowed to stir 5.07 g of this compound in 500 ml of Me-

Warm up slowly to 20 ° over the course of 30 minutes, then add 5.0 g of potassium carbonate to ethanol

Ice and water are added and, after a further 20 50 ml of water, the mixture is heated in a bath at 80 ° for 1 hour.

2 hours with benzene. The extracts are then evaporated in a water jet vacuum up to

2N hydrochloric acid and ice-cold 5 ° / ₀ sodium bicarbonate crystallisation, taken up in methylene chloride and

solution washed, dried and washed in a water jet, the organic solution with water, dried

vacuum evaporated. 17.5 g of J ' ^l -3-Oxo are obtained and evaporated, 4.52 g of crude, crystalline

6 _J 5,19-oxido-17 _/ S-decanoyloxy-androstene (6 / 9,19-oxido-95 ized 3 /? - hydroxy-5 <x-bromo-6 / 9,19-oxido-17-oxo- at-

testosterone caprinate) as a light oil. drostan, which after dissolving from methylene chloride

Analogous esterification of the 6 / ?, 19-Oxido-testo-ether at 214 to 218 ° melts (conversion from

sterons with / 3-phenylpropionic acid chloride are obtained 188 °); [oc] d = + 47.1 ° (in chloroform); in IR

the <d ⁴ -3-Oxo-6 / ?, 19-oxido-17 / S- ( _j e-phenyl-propionyl spectrum, among other things, bands at 2.75, 5.75,

oxy) sand as an almost colorless oil. 30 6.69, 9.52, 9.79, 10.06 and 11.05 µ.

2.0 g of 6 / J, 19-Oxido-testosterone are mixed in a mix of the following, with benzene and benzene-vinegar-

Mixing of 10 ml of pyridine and 10 ml of acetic acid ester mixtures, the eluted fraction is isolated by

anhydride dissolved. The mixture is heated to 60 ° for 3 hours. Crystallization from methanol or methylene chloride.

and then evaporated in a water jet vacuum. Through ether a compound that melts at 219 to 221 °

Crystallization of the residue from ether wins 35 of the formula C ₂₁ H ₃₀ O ₄ ; [oc] o - -8.7 ° (in chloroform),

one 1.82 gz) ⁴ -3-Oxo-6 / ?, 19-oxido-17j? -acetoxy-an- The compound shows in the IR spectrum among other things

drosten from the F. 149 to 152 °; [<% b = - 96 ° (in chloro bands at 5.96, 7.26, 7.31, 8.10, 9.73 and 11.52 μ.

form), UV maximum at 238 ηαμ (ε = 13 200). 700 mg 3/3-hydroxy-5ix-bromo-6 / 3,19-oxido-17-oxo-

IR bands at 5.76, 5.96, 6.73, 7.27, androstane, among others, are dissolved in 35 ml of acetone, and after

8.09, 9.10, 9.17, 9.26 and 11.42 µ. ₄₀ Cooling the solution to 0 ° is given 1.0 ml of a

g) 940 mg of ^{I 4} -3,17-dioxo-6 / 5,19-oxido-androstening with water to 50.0 ml of a diluted solution of are dissolved in 50 ml of methanol. 100 ml of sodium borohydride and acid are added to the 13.3 g of chromium trioxide in 11.5 ml of concentrated sulfur-cooled solution at -20 °, and the mixture is stirred at 0 ° for 15 minutes. Then dissolved in 2.5 ml of 2N sodium hydroxide solution. Then, one sets with a solution of 8.0 g of crystallized 2 hours at -20 °, treated with 10 ml of sodium acetate and 15 ml of water, diluted with benzene 2N sulfuric acid and 30 ml of water and distilled and washed the separated organic layer with methanol in a water jet vacuum. The out- water. The residue of the dried benzene precipitated product is dissolved in methylene chloride and is obtained by crystallization from methylene, the organic solution is washed with water, 570 mg of the pure chloride-ether, in Example 2, dried and evaporated. The crystalline back 50 part b) described zK3,17-Dioxo-6 / S, 19-oxido-anstand is stirred with 100 ml of benzene for 1 hour, then at the m.p. 184 to 186 °.
if the insoluble ⁴ -3,17 / 9-dihydroxy-

6 / J, 19-oxido-androsten (360mg) by filtration. Example 4
The pure connection melts after releasing

Methylene chloride-methanol at 221-222 °; [<x] _D 55 10.0 g mercury diacetate and 3.0 g calcium

= + 48.6 ° (in chloroform-alcohol 1: 1). carbonate are suspended in 200 ml of cyclohexane;

The benzene filtrate is evaporated to dryness and the reaction mixture is after addition of 2.5 g

the residue (598 mg) recrystallizes from acetone. 3j8-acetoxy-5'-chloro-6 /? - hydroxy-17-oxo-androstane

346 mg of pure ⁴ -3-oxo-6 / 5,19-oxido- and 11.0 g of iodine are obtained for 1 hour with stirring and exposure to light

17/3-hydroxy-androstene from 78 to 80 °. 60 heated to the boil with a 500 watt lamp. Included

abundant red mercury iodide is deposited. Man

Example 3 cools down, the precipitate is separated off by filtration

and washes with cyclohexane. The filtrate will

59.4 g of lead tetraacetate and 27 g of calcium carbonate with 5 ° / _o potassium iodide solution, dried with Na

are decolorized in 2430 ml of cyclohexane for 30 minutes to boiling 65 trium thiosulfate and after washing with

heated; 13.45 g of crude 3/3-acetoxy-water are then added, dried and evaporated. You get

5 <x-bromo-6 /? - hydroxy-17-oxo-androstane and 17.5 g of iodine, 2.97 g of crystallized crude product, from which through

and boils under exposure to a 500 watt dissolution of ether — hexane 1.70 g of pure 3/9-acetoxy

13 14

/ ^ from F. 180 wash, dried and evaporated in vacuo,

Insulate up to 182 °. 620 mg of the low volatility,

aromatic smelling oil mixed amorphous

B e i s ρ i e 1 5 S ^ / S-Diacetoxy-SiX-chloro-o / ^ - oxido-aodrostans,

A suspension of 5.0 g of silver acetate and 2.5 g of 5 which is purified on aluminum oxide. The pure

3ß-Acetoxy-5 * -chlor-6 / Miydroxy-17-oxo-androstane melts in combination, crystallized from alcohol, at

200 ml of cyclohexane is 160 to 161 ° after adding 4.5 g of iodine. Connect in the IR spectrum of the connection,

heated to boiling with exposure and stirring. After the strong acetate absorption at 5.76, 8.16

It is cooled for 2 hours, rewashed with cyclohexane and 9.65 μ absorption bands at 6.72, 10.60, 10.75

and decolorize the filtrate by shaking it out with ver io and 12.51 μ.

thin thiosulphate solution and water. By adding 870mg of crude 3ß, nß'Oiacetoxy'5a-cblor-6ßA9-ox-

Evaporation of the cyclohexane solution gives 2.82 g of ido-androstane are dissolved in 50 ml of methanol, with

crystallized residue, which is mixed with a little oily 250 mg of sodium hydroxide in 1 ml of water

By-products mainly from the 3 ^ -Acetoxy- and left to stand for 3 days at 25 °. After adding

5x-chloro-6 / 3,19-oxido-17-oxo-androstane consists. The methyl alcohol is removed in vacuo by water

Crystallization from ether-hexane is obtained 1.95 g evaporated, the residue in ether-methylene chloride

the pure connection from the F. 180 to 182 °. absorbed, washed neutral with water and how

usually isolated. 680 mg of crystalline material are obtained

Example 6 S / i.n / i-Dihydroxy-SiX-chloro-o / ^ - oxido-androstane.

»O After one recrystallization, the compound melts

2.5 g S / J-acetoxy-SÄ-chloro-ojS-hydroxy-n-oxo connection at 220 to 224 °. The IR spectrum shows drostan, 3.0 g calcium carbonate, 5.0 g N-iodosuccine - among other things, absorption bands at 2.76, 6.75, 7.00, imide and 2.85 g iodine are in 200 ml cyclohexane 7 , 30, 9.55, 9.76, 10.62, 10.90, 11.70 and 12.60 µ.
suspended; the mixture is heated to boiling for 3 hours b) 80 mg S / ^ njff-dihydroxy-Sa-chloro-o / i. ^ - oxid under exposure to light and stirring. 25 androstane, dissolved in 5 ml of pyridine, are mixed with a. After 1.5 hours, a further 5.0 g of N-iodine mixture of 200 mg of chromium (VI) oxide and 5 ml of succinimide are added. After the reaction time has elapsed, pyridine is added and the mixture is cooled for 20 hours while stirring, the precipitate is filtered off and washed 45 to 50 ". The in Example 1. Part b), with cyclohexane. The filtrate is worked up with potassium schricbene and Subsequent umiodide solution, sodium thiosulfate solution and water crystallization from methylene chloride — methanol gives washing, drying and 45 mg / 1 "-3,17-dioxo-6ß, 19-oxido-androsten evaporated from the F. in a water jet vacuum. 824 mg of S / i-acetoxy-Soc-chloro-184 to 186 "are obtained. This is similar to the product described in Example 2, part b), öß. ^ - oxido-n-oxo-androstane. The filter residue in every respect identical,
is extracted with 250 ml of methylene chloride and c) treated, 1 g of the extract described in part a) is washed like the above cyclohexane filtrate, 35 3 / 9.17 (Ö-diacetoxy-5 * -chlor-6 / 9,19-oxido -androstane, dried and evaporated.The residue (1.812 g) dissolved in 25 ml of glacial acetic acid, at 85 to 90 ° in the manner described in the enclosed by crystallization from ether 1.45 g of pure game 2, part d), with 1.5 g chromium starting material with a melting point of 225 to 227 °. trioxide, 0.88 g of lactone of 30.17 / 9-di-

acetoxy-Sa-chloro-o / S-hydroxy-androstane - ^ - acid vom

Example? 40 F. 185 to 186 °.

2.5 g Sß-Acetoxy-Sa-chlor-o / J-hydroxy-n-oxo-an-

drostan are suspended in 200 ml of cyclohexane, 22 g of lead tetraacetate and 10 g of calcium carbonate are

and after adding 3.0 g of calcium carbonate, 4.0 g of the in 900 ml of cyclohexane for 30 minutes with stirring

N-bromosuccinimide and 2.85 g of iodine heated to the boil for 2 hours. Then you give 5.0 g of 3 / 9.17ß-Di-

with exposure to light and stirring on the reflux condenser acetoxy-5 "-bromo-6je-hydroxy-androstane and 6.4 g of iodine

cooked. Then you work, as in Example 6, to and heat with exposure to a 500 watt

wrote on. 3.128 g of an oil are obtained, which lamp and stirring for 1 hour to boil. then

crystallized on addition of ether-hexane. It is cooled, the colorless solution is filtered and the

Purification, a benzene solution of the filtrate is filtered, washed with water, dried and im

Crude product through 25 g of aluminum oxide and washes evaporated with a water jet vacuum. 5.53 g are obtained

well with benzene (400 ml in total). The crude product is obtained which is in a benzene-hexane (1: 4) mixture

such a residue (2.74 g), which is mainly dissolved and filtered through 100 g of aluminum oxide,

the S / J-Acetoxy-Sa-chlor-o / Ug-oxido-n-oxo-an · With benzene-hexane (1: 4) and (1: 1) mixture as well

drostan exists. By crystallization from ether with pure benzene 3.4 g of substance are eluted.

Hexane is isolated the pure compound from F. 180 By crystallization from methylene chloride-ether-

up to 182 °. Hexane gives 2.6 g of pure 3β, 7β-diatxtoxy-5 <x ~

Example 8 bromo-6 / S, 19-oxido-androstane with a melting point of 178 ° to 180 °;

[&] d = -5.4 "(in chloroform); IR spectrum below

a) 150 ml cyclohexane, 1.0 g calcium carbonate, 3.0 g 60 other bands at 5.78, 6.69, 7.30, 8.10, 9.12, 9.63,

Lead tetraacetate and 980 mg iodine are V ₂ hours in 9.75 and 10.93 μ.

Heated in the dark to 80 ° with stirring. After adding 2.236 g of this compound to 225 ml of 500 mg of dßMß-di & cetoxy-soi-chloro-eß-hy- methanol, after adding a solution of 2.25 g of hydroxy-androstane, the reaction mixture potassium carbonate is boiled in 22.5 mg Water was further refluxed for 1 hour until decolorization (1.5 to 2.5 hours). The reaction reflux is then cooled. The cooled solution is filtered, the mixture is washed off and evaporated in a water jet vacuum until residue is washed out with ether, the filtrate with for crystallization, takes up in methylene chloride 10% sodium thiosulfate solution and water and methanol (3: 1) mixture washes with water.

Evaporation of the dried organic solution gives 1.83 g of pure 3 / S, 17 /? - dihydroxy-5 «-bromo-6 ^, 19-oxido-androstene from m.p. 235 to 236 °; Mo = -8.7 ° (in chloroform); IR bands (in Nujol) among others at 2.93, 6.70, 7.72, 8.61, 9.03, 9.38, 11.08, 11.76 and 12.69 μ.

500 mg of crude 3ß, 17/3 - dihydroxy -5x- bromo - 6ß, 19-oxido-androstane are dissolved in 50 ml of acetone. 1.0 ml of a solution of 13.3 g of chromium trioxide in 11.5 ml of concentrated sulfuric acid, which is made up to 50 ml with water, is added to the solution, which has been cooled to 0 °, and the mixture is stirred at 0 ° for 25 minutes. 8.0 g of crystallized sodium acetate and 15 ml of water are then added, the mixture is diluted with benzene, the organic layer is washed with water and the dried benzene solution is evaporated to dryness in a water-jet vacuum. 339 mg of the pure Δ '-3,17-DiOXO-O / ?, 19-oxido-androsteus with a melting point of 184 ° to 186 ° are obtained from the residue (409 mg) by crystallization from methylene chloride-ether.

Example 10

a) First 8.0 g of iodine and then 5 g of S / S ^ O / I-diacetoxy-six-chloro-eß-hydroxy are added to a suspension, heated to 80 °, of 10 g of calcium carbonate and 30 g of blood tetraacetate in 1000 ml of cyclohexane -pregnan and the reaction mixture is refluxed for 3 hours. Then, as described in Example 1, part a), worked up. 6.1 g of a solid crude product are obtained, from which the pure 3β, 20 /? -Diacctoxy-5 "v-chloro-6/19-oxido-pregnane is obtained by crystallization from acetone-hexa. It melts at 148 to 150 °, [oc] _D = + 25 ° (in chloroform).

4.0 g of this compound are dissolved in methanol and, after adding 4.0 g of potassium carbonate and Water boiled under reflux for 1 hour. Then it is evaporated in a water jet vacuum and isolated from the residue in the usual way the crude Sß ^ O / S-dihydroxy-Sa-cMor-o / ^ lP-oxido-pregaen, which melts at 237 to 240 °.

1.0 g of this compound is stirred in 50 ml of pyridine after adding 2.2 g of chromium trioxide for 20 hours at 60 °. Then, as described in Example 1, part b), worked up. A crystallized residue is obtained from which the pure zl ⁴ -3,20-dioxo-6β, 19-oxido-prene (6 / 9,19-oxidoprogesterone) with a melting point of 142 ° to 143 ° can be isolated by dissolving; [ _X ] _D = -18.8 "(in chloroform).

b) 1.0 g of the 3 / 3.20 / J-diacetoxy-5a> chloro-6 / ?, 19-oxido-pregnans described in part a) is oxidized in 30 ml of glacial acetic acid after adding a solution of 1.5 g of chromium trioxide in 1.5 ml of water at 70 ° for 20 minutes. After working up, as described in Example 2, part d), a crude product is obtained from which by dissolving from methylene chloride-ether the pure 19.6 /? - lactone of 3, S, 20 /? - diacetoxy-5Ä-chloro-6 /? - hydroxy-pregnan-19-acid from the F. 189 to 190 ° can gain.

Example 11

a) A suspension of 110 g of lead tetraacetate and 50 g of dry calcium carbonate is heated in 4.5 l of cyclohexane with stirring for about 40 minutes to the boil. Then 25 g of 3 /? - acetoxy-5 «-chloro-6 /? - hydroxy-20-oxo-pregnane are added and 32 g of iodine and keeps the solution under exposure to a 1000 watt lamp and with stirring for so long in the Simmer until the iodine color has completely disappeared (about 30 to 90 minutes). It is then cooled and filtered the undissolved salts and washes the filter residue with cyclohexane. The filtrate is diluted with Sodium thiosulfa solution and washed with water, dried and evaporated in a water jet vacuum. Crystallization of the crude product from ether gives 19.2 g of pure Sß-acetoxy-Sa-chloro-eß. ^ - oxido-20-oxo-pregnane from 150 to 153 °. From the

ίο Mother liquor can be obtained a further 3.3 g of somewhat less pure substance. The pure compound shows a [x] d = + 65 ° (in chloroform) and in the TR spectrum, among other things, bands at 5.78, 5.88, 6.70, 8.13, 9.12, 9.66, 10.60, 10.86 and 11.75 µ.

In an analogous manner, 3 / f, 17o> diacetoxy- 5x- chloro- 6ß -hydroxy-20-oxo-pregnane is obtained 3j3,17a-diacetoxy-6 ^, 19-oxido-20-oxo-pregnane from F. 187 to 187.5 ° and from the 3 / $ - acetoxy-5 "-chlor-6 /? - hydroxy-17" -valerianyloxy-20-oxo-pregnan the 3 | 3-acetoxy-5ix-chloro-6 /? , 19-oxido-17a-valerianyloxy-20-oxo-pregnane; IR spectrally bound at 5.75, 5.84, 6.72, 8.21, 9.70 and 10.85 µ.

The chlorohydrin used as the starting material is prepared as follows: 150 g of pregnenolone acetate are dissolved in 5000 ml of ether; 150 g of chlorinated lime (containing 30% active chlorine) and 8,200 ml of water are then added and the reaction mixture is vigorously stirred. After 5 minutes, 105 ml of glacial acetic acid are added and, after a further 25 minutes, 500 ml of 10 ^u / ₀ strength potassium iodide solution are added. Finally, the aqueous layer is separated, the ethereal solution is washed with 10 ° / ₀ sodium thiosulfate solution, diluted Natriunibicarbonatlösung and with water, dried, and evaporated under Wasserstrahlvakuuin. The residue is mixed with 800 ml of acetone and left to stand at 0 ° overnight. First 47.5 g are obtained, and a further 58 g from the mother liquor of the Iß- acetoxy-5iX-chloro-6 /? - hydroxy-20-oxo-pregnane, which melts at 196 ° to 197 ° after being dissolved from acetone; [ot] _D = + 25.5 ° (in chloroform); in the IR spectrum the compound shows, inter alia, bands at 2.75, 5.78, 5.88, 8.12, 8.68, 9.68 and 9.72 μ.

In an analogous manner, 17x-acetoxypregnenolone acetate is produced by addition of hypochlorous acid, the 3 / ?, 17 "; - diacetoxy-5a-chloro-6 ^ -hydroxy-20-oxo-prgnane.

b) 10.0 g of 3 / i? -acetoxy-5Ä-chloro-6 _/ S, 19-oxido-20-oxopregnane are dissolved in 180 ml of acetic anhydride after adding 4.0 g of p-toluenesulphonic acid in one to 140 to 150 ° heated bath heated for 4 hours at a pressure of 50 to 60 mm Hg, with 90 ml of solvent being distilled off. It is then cooled, the reaction mixture is poured onto ice and

Water and extracted with an ether-methylene chloride (3: 1) mixture. The extracts are washed with sodium bicarbonate solution and water, dried and evaporated. The residue (10.40 g) is dissolved in benzene and the solution is filtered through 100 g of aluminum oxide. From the eluates is obtained 10.1 g of crude product, which still contains about 15 ° / ₀ starting material. The pure Δ "(^ -S / WO-diacetoxy-SiX-chloro-ß, 19-oxido-pregnen from F. 171 to 172";[<x] _D = +18 , 4 ° (in chloroform) In the IR spectrum, the compound shows, inter alia, bands at 5.76, 6.70, 7.30, 8.16, 9.13, 10.60 and 10.87 μ.

17 18

10.1 g of crude A ¹⁷ («·) -3 / 2,20-diacetoxy-5« -chloride at 40 to 50 ° in 40 ml of acetic anhydride and

6jS, 19-oxido-pregnen are dissolved in 250 ml of benzene, 4.0 g of p-toluenesulfonic acid are added. The response

and after adding 240 ml of an ethereal solution mixture is cooled to a mixture of

of perbenzoic acid (containing 2 molar equivalents per- 1000 ml of ice water and 10 ml of pyridine poured, and

acid, based on the enol acetate) is left for 5 hours, and the product is separated out after 15 minutes

standing at room temperature. After this time of stirring, filtered off. The back washed with water

70.2% of the calculation for complete oxidation is taken up in ether, the solution

A small amount of peracid is consumed. The diluted, washed neutral, dried and evaporated. the end

Reaction mixture with ice water, extracted with ether the residue (3.85 g) is obtained by crystallization

and washes the extracts with water, sodium to sation from ether — petroleum ether 3.0 g 3 / ?, 17 <x -diacet-

bicarbonate solution and water. From the dried oxy-5Ä-chloro-6 / ?, 19-oxido-20-oxo-preg) ian from F. 187

Ether solution gives 9.90 g of crude epoxy. That up to 187.5 °.

pure 3 / 3.20 - diacetoxy - 5λ - chlorine -6 / S, 19; 17 ", 20-to-2.8 g of this compound are in 100 ml of methanol

After crystallization, oxido-pregnan melts after adding 500 mg of potassium carbonate in 2.5 ml

Methylene chloride-ether at 192 to 194 °; [oc] d i5 water was stirred for 13 hours at room temperature.

= + 14.4 ° (in chloroform). The compound shows Then you dilute with water, this is distilled

in the IR spectrum, inter alia, bands at 5.76, methanol in a water jet vacuum, extracted with

6.70, 7.30, 8.13, 8.58, 9.67, 10.66 and 10.81 µ. Ether, washes the extracts with water, dries them

10.0 g of crude 3 / ?, 20-diacetoxy-5 * -chlor-6 / U9; 17 *, and evaporated. The residue (2.52 g) delivers

20-bisoxido-pregnane in 800 ml alcohol with 20 crystallization from methylene chloride-methanol 1.98 g

45 ml of a 2.4 ° / _o strength aqueous sodium hydroxide 1 hour S / S-hydroxy-sit-crilor-oftw-oxido-Na-acetoxy ^ O-oxo-

left to stand at room temperature. After the addition of pregnan from 238 to 251 °. When you repeat

500 ml of water are evaporated in a water jet recrystallization, the temperature rises to 243 to 245 °.

vacuum to half the volume, heated 425 mg of this compound in 15 ml of acetone

for 3 hours at 60 °, filtered the precipitate 25 dissolved and at -5 to -6 ° with 0.5 ml of one with

off, wash it well with water and dry water on 50 ml of a dilute solution of 13.3 g

the filter residue. 9.85 g of crude product are obtained. Chromium trioxide in J 1.5 ml of concentrated sulfuric acid

Added by crystallization from methylene chloride — methanol. The mixture is stirred for 30 minutes at -5 °, a solution is

3.90 g of the pure 3 / f, 17A dihydroxylation of 5.5 g of crystallized sodium acetate are obtained in 10 ml

5a-chloro-6 / ?, 19-oxido-20-oxo-pregnans from F. 251 to 30 water and 35 ml of benzene. After detaching

253 °; [<x] d = + 22.4 ° (in chloroform-alcohol). the organic phase is washed with half

Another saturated sodium chloride solution separates out of the mother liquor, dries and evaporates in the

binding from mp 251 to 253 °, at which it is a water jet vacuum. 450 mg of raw material are obtained

a rearrangement product of the above diol han- 3,20-DiOXO-Sa-ChIOr-O / ?,] 9-oxido-17a-acetoxy-pregnaii.

yours 35 The crystallized from methylene chloride-petroleum ether

200 mg S & na-dihydroxy-SiX-chloro-o / S ^ -oxido- ^{s' erte reme} compound melts at 156 to 158 °

20-oxo-pregnane are dissolved in 1.0 ml of acetic anhydride (decomposition), re-solidifies and then melts at

and 1.0 ml of pyridine stirred for 14 hours, the 185 to 190 °. IR bands among others at 5.84,

Starting material slowly goes into solution. Then 6.75, 6.82, 7.35, 8.15, 8.30, 9.10, 9.32, 9.70, 10.35 and

it is poured onto ice water and extracted with a 40 11.00 μ.

Ether-methylene chloride mixture. From the with water, 350 mg of 3,20-Dioxo-5 "-chlor-6 ^, 19-oxido-17" -acet-

Hydrochloric acid, bicarbonate solution and water washed oxy-regnan are dissolved in 100 ml of methanol, and

and dried extracts, 210 mg of raw material are obtained after adding 600 mg of potassium acetate in 70 ml

product and by crystallization from ether-petroleum-water, one first distills about the

ether 185 mg of the pure S / S-acetoxy-Soc-chlorine-45 half of the solvent and finally evaporated

6 / U9-oxido-17a-hydroxy-20-oxo-pregnans vom F. 166 in a water jet vacuum to dryness. Then solve

up to 167 °. The compound is occasionally crystallized, the residue in 70 ml of water and a gel

in a modification that melts up to about 175 °. mixture of ether-methylene chloride (3: 1), washes

[«] /) = -2.1 ° (in chloroform). In the IR spectrum, the organic phase with water, dries and

one finds bands among others at 2.74, 2.82, 50 evaporates. 308 mg of crude product are obtained from which

5.76, 5.85, 6.69, 7.30, 8.10, 9.65 and 10.86 µ. by dissolving ether — petroleum ether in two

100 mg of S / ^ noc-dihydroxy-Scx-chloro-ö / ii ^ -oxido- portions together 275 mg of pure zH-3,20-dioxo-20-oxo-pregnane are dissolved in 1.0 ml of acetic anhydride 6 / 3.19 -oxido-17 (X-acetoxy-20-oxo-pregnen from the F. 190 after the addition of 100 mg p-toluenesulfonic acid 2.5 hours to 192 °. [k] d = -109 ° (in Chloroden at 40 The mixture is then poured onto a mixture (55 form); the IR spectrum shows the compound under 50 ml of ice water and 0.5 ml of pyridine, diluted with other bands at 5.75, 5.82, 5.98, 7, 30, 8.07, 8.35, after 10 minutes with ether and washes the extracts 9.07, 9.75, 10.35, 10.55, 11.37 and 12.30 µ.
with sodium bicarbonate solution and with water. By c) 10 g of the 3 / 3,20-diacetoxy crystallization of the evaporation residues (106 mg) obtained in part b) from 5'-chloro-6 / S, 19; 17a, 20-bisoxido-pregnans with ether-petroleum ether 98 mg of pure 3 / ?, 17a-Di- 60 100 ml of glacial acetic acid-water (2: 1) are obtained, and acetoxy-5'-chloro-6 ^, 19-oxido-20-oxo-pregnane from F. on for 1 hour heated in the boiling water bath. Then 187 to 187.5 °; [<x] p = -6.2 ° (in chloroform). This is cooled, mixed with 250 ml of water and the connection shows in the IR spectrum, inter alia, vacuum, the acetic acid is distilled off. The residue bands at 5.77, 6.68, 7.79, 8.10, 9.65, 10.39 and is in a methylene chloride-ether mixture to -10.85 μ. 65 taken, the solution washed with water,

The same compound is also obtained by drying and evaporating. The return thus obtained

Acetylation of 4.0 g of S / J-Acetoxy-Sa-chloro-ojö. ^ - ox- stand is dissolved in hot methanol and left to stand,

ido-17 «-hydroxy-20-oxo-pregnane for 2.5 hours after which 4.2 g of 3/3-acetoxy-Sa-chloro-o / i, 19-OXJdO-Ha-IIy-

I 192 193

19 20

Crystallize droxy-20-oxo-pregnane. According to Chromate- BeisDiel 13

graphy on silica gel and crystallization from methylene

chloride — methanol melts the pure product at 3 g / yy.

175 to 176 °. 20-oxo-5 "-pregnan are, as in Example 8, part a),

d) 2.5 g of Sß.na-diacetoxy-Sa-cnlor-oßliJ-oxido-5 described, with lead tetraacetate and iodine in cyclohexane 20-oxo-pregnane are dissolved in 50 ml of glacial acetic acid. Too implemented. This gives 3.5 g of a crude product, the solution heated to 70 ° is added. while stirring from which the 3/3-acetoxy-5 "-chlor-6 / ?, 19; 16.17 "-to within of about 4 minutes a solution of 3.75 g of oxido-20-oxo-pregnane by crystallization from a Cliromtrioxyd can be isolated in 3.75 ml of water and 30 ml of glacial acetic acid, methylene chloride-ether mixture. It and stir for a further 30 minutes at 70 °. Then cools io melts at 230 to 233 °; [a] j> = + 36.3 ° (in chloroman from, pours on water and sucks the precipitated form).

white crystals. 2.48 g of crude 19.6 / 3-Lac by saponification with potassium carbonate in methanol are obtained

tone of the 3β, 17oc-diacetoxy-5 «-chlor-6/5-hydroxy-20-oxo- to the 3/3 - hydroxy - 5λ - chlorine - 6β, 19; 16.17a - bisoxide o-

pregnan-19-acid from m.p. 215 to 219 °. The from 20-oxo-5a-pregnane and subsequent oxidation of the

Methylene chloride-ether recrystallized pure ver 15 at 241 to 247 ° melting crude product with

bond melts at 235 to 237 °. IR bands under chromium trioxide in pyridine, as in Example 10, part a),

others at 5.64 μ (γ lactone); 5.80 μ (acetates indicated, you get the / J ⁴ -3,20-Dioxo-6 / 9.19;

+ 20-ketone); 8.08, 9.05, 9.16, 9.25, 9.60, 10.34, 10.78 16.17 <x-bisoxido-pregnen (6 / 3.19; 16.17ix-bisoxido-pro -

and 12.07 µ. gesteron), which melts at 154 to 156 °.

1.7 g of 19,6ß-lactone of S & na-diacetoxy-Sa-chloro- ^a0 The 5 ″ -Chlorverbin-6 / Miydroxy-20-oxo-pregnan-19-acid used as starting material are dung in 104 ml by addition of hypochlorous acid methanol after adding 340 mg of sodium bicarbonate to the known zl ^s -3 /? - acetoxy-16.17 <% - oxido-20-oxonate and 3.1 ml of water for 45 minutes in one pregnen (analogous to the example 1, part a) described), stirred to 70 ° heated bath. Then you cool down, made. The pure S / S-acetoxy-Sa-chloro-ö / S-hydroxy mixed with 500 ml of water and extracted with ether. 35 16,17a-oxido-20-oxo-5 "-pregnane melts after being washed with water and dried from acetone-hexane at 194 ° to 198 °; Extracts give 1.57 g of crude 19.6 ^ lactone of [<x] d - -7.8 ° (in chloroform).
3 / 9.6 / 3 - dihydroxy-5α-chloro-17α-acetoxy-20-oxo-pregnane-19-acid, which after dissolving from methylene Example 14
chloride ether melts at 246 to 248 °. 30th

5.0 g mercury (II) acetate and 2.5 g 3 / S-acetoxy

For example 12 5 «-chlor-6 / S-hydroxy-17-oxo-androstane are used in

100 ml of carbon tetrachloride suspended. Towards-

5.0 g of the 18.20-lactone of S / I-acetoxy-Sa-chloro would give 3.85 g of iodine and boil the mixture under 6 / 3.20 / 9-dihydroxy-5Ä-pregnan-18-acid are in 1.5 1 35 exposures with a 500 watt lamp during a cyclohexane with lead tetraacetate and iodine, as in the hour under reflux, which is described according to VerBe Example 8, part a), reacted. A further 1.9 g of iodine are added from the dwindling iodine color (after about 10 to 15 minutes) in the manner indicated there. During the reaction time, pure red mercury (II) iodide is obtained by crystallization from benzene. 18,20-Lacton der S / J-Acetoxy-Sa-chlor-o / S. ^ - oxido- 40 The cooled solution is filtered, the residue 20 /? - hydroxy-5i% -pregnan-18-acid from F. 229 to 234 °; washed with carbon tetrachloride and the filtrate [e-fo = -48.3 ° (in chloroform). with potassium iodide solution and thiosulphate solution

Wash by saponification with potassium carbonate in methanol, dried and evaporated. Received from the return the 3 / 3.20 / 5-distant 18,20-lactone (2.63 g) is obtained therefrom by crystallization hydroxy-5a-chloro-6 / 3,19-oxido-5a-pregnane-18-acid, 45 ether-hexane 2.16 g of pure 3 /? - acetoxy-5a-chlorowhich directly with chromic acid-sulfuric acid in 6 / J, 19-oxido-17-oxo-androstane with a melting point of 180 to 182 °. Acetone at 0 ° to the crude 18,20-lactone of the 3-oxo-

5a-chloro-6 ^, 19-oxido-20 ^ -hydroxy-5a-pregnan-18-acid Example 15
is oxidized. This becomes through 1 hour

Boiling in pyridine hydrochloric acid, and heating a suspension of 5.0 g of mercury

this gives the 18,20-lactone of ^{I 4} -3-oxo-6, Ö, 19-oxido-silver (II) -acetate and 2.5 g of S / S-acetoxy-Sa-chloro-ojö-hy-

20/3-hydroxy-pregnen-i 8-acid, which after um- droxy-17-oxo-androstane in 100 ml carbon tetrachloride

dissolve from methylene chloride ether at 259 to 260 ° after adding 3.98 g of iodine in the dark during

melts; [<x] b = -111 ° (in chloroform). 16 hours to boil and then works the purple one

The 5a-chlorine solution used as starting material, as described in Example 14, is obtained in this way

6 / i-hydroxy compound is, as in Example 1, part a), one 2.72 g of a crystallized crude product, which

described by the addition of hypochlorite in the IR spectrum in the CO area next to the band des

Acid to the 18,20-lactone of the Δ ^G -3 /? - acetoxy-20ß-hy-17-ketone and of the 3-acetate at 5.80 μ a clear

droxy-pregnen-18-acid produced. This compound shows band at 5.60 μ and the main thing is that by treating the Δ ⁵ -3 / 3-acetoxy-20 / S-hy- 60 the S / S-acetoxy-Sa-chloro-o / S. ^ -oxido-n-oxo-andro-

droxy-pregnens with lead octraacetate and iodine in a boiling pot. But the crude product also contains

the cyclohexane and subsequent oxidation with a small amount of the 19,6 / 5-lactone of the 3/9-acetoxy

Chromium trioxide and pyridine with the addition of silver-Sa-chloro-o / J-hydroxy-n-oxo-androstane - ^ - acid.

chromate produced at 60 °. The pure 18,20 lactone. . .

the 3 / S-acetoxy-5'-chloro-6 /? - hydroxy-20 /? - hydroxy-65 Example 16

5 «-pregnan-18-acid melts after dissolving into a solution of 5.0 g iodine in 400 ml Tctrachlor-

Methylene chloride-ether at 227 to 228 °; [x] d carbon is added 40 g of S / J-acetoxy-Sa-chloro-

= -48.3 ° (in chloroform). 6 /? - hydroxy-17-oxo-androstane and 70 g of blood tetraacetate

(containing 7 g of glacial acetic acid) and the mixture is heated to boiling while stirring. In the course of the reaction the iodine color disappears almost completely. The mixture is then cooled to room temperature off, filtered off the lead salts and washed the reddish filtrate one after the other with aqueous solution Sodium thiosulfate solution, dilute soda solution and water. Finally, the colorless carbon tetrachloride solution is filtered of a little precipitated lead iodide and the filtrate is evaporated to dryness.

The crystallized residue (about 40 g) is briefly boiled in 80 ml of methanol and after a while Standing at 0 to 5 ° sucked off.

This gives 32 to 34 g of pure white 3 /? - acetoxy-5-x-chloro-6,19-oxido-17-oxo-androstane from 180 to 182 ° (sintering from 170 °).

Example 17

2.5 g of S / Sn / I-diacetoxy-ojÖ-hydroxy-androstane, 5 g of mercury (II) acetate and 3.9 g of iodine are poured over with 100 ml of carbon tetrachloride. The suspension is refluxed for 2 hours in the dark with stirring, the solution is nitrated and the insoluble part is washed with carbon tetrachloride. The carbon tetrachloride solution is washed with a solution of 1 g of potassium iodide and 10 g of sodium thiosulfate in 50 ml of water, then with water, dried and evaporated in vacuo. The residue is dissolved in 40 ml of glacial acetic acid and the solution is shaken with a total of 20 g of small portions of zinc powder for 20 minutes below 20 °. The zinc is then suction filtered and washed with acetone. The concentrated solution is mixed with ethyl acetate, the ethyl acetate solution is washed with water, dilute hydrochloric acid and water, dried and evaporated in vacuo. The residue is chromatographed on 75 g of aluminum oxide (II). From the residue of the evaporated Benzoleluate pentane mixture of isopropyl ether-1,219 g can be of the 3 / 9,170-diacetoxy-6 /}, 19-oxido-androstans ^vc> m 144 F. gain to 146 ° on recrystallisation from a.

The residue of the evaporated ether eluates can be recrystallized from methylene chloride- Isopropyl ether 250 mg of 3 //, 17 /? - diacetoxy-6-oxo-androstane win from F. 178 to 179.

Example 18

2.5 g 3 / 9.17 / 3-diacetoxy-6 (S-hydroxy-androstane, 5.0 g Silver acetate and 4.4 g of iodine are poured over with 200 ml of cyclohexane. The suspension is stirring with a 250 watt »ML. Mixed-light lamp "(vonPhilips) irradiated and at the same time refluxed for 2 hours cooked. The suspension is filtered off with suction, the insoluble salts are washed with cyclohexane and the filtrates are shaken with a solution of 1 g of potassium iodide and 10 g of sodium thiosulfate in 50 ml of water, then with water, dries and evaporates in a vacuum. The residue is treated with zinc and glacial acetic acid and recovered then the reaction product, as indicated in Example 17. On recrystallization from isopropyl ether — Pentane 1.38 g of 3 ^, 17 /? - diacetoxy-6 ^, 19-oxidoandrostane are obtained from F. 143 to 145 °.

The mother liquors are then chromatographed on 40 g of aluminum oxide (II). From the residue of the Benzene eluates can be obtained by recrystallization (as above) 580 mg of the 6 / ?, 19-Äthcrs from F. 144 to 146 ° win.

As indicated in Example 18, 100 mg of 3 ^, 17/3-diacetoxy-6-oxo-androstane can also be obtained from the ether eluates from F. 178 to 179 ° win.

Example 19

g lead tetraacetate and 5 g calcium carbonate are mixed with 500 ml cyclohexane for 10 minutes Boiled reflux with stirring. Then you add 2.5 g of 3 / f, 17jß-diacetoxy-6 /? - hydroxy-androstane and 4 g

ίο Iodine and reflux for a further 2 ¹ I ₂ hours. The suspension is then suction filtered. The insoluble parts are then washed with ether and the organic solution is worked up as indicated in Example 18. After the zinc-glacial acetic acid treatment, 1.87 g of crystals of 3 / 3,17j3-diacetoxy-6 / 3,19-oxido-androstane with a melting point of 143 to 145 ° are obtained. After chromatographic separation of the mother liquors, 240 mg of the same 6 / ?, 19 ether with a melting point of 144 to 146 ° are obtained.

Example 20

2.5 g S / ^ n / S-diacetoxy-oß-hydroxy-androstane, 3 g Calcium carbonate, 5 g of N-iodosuccinimide and 2.85 g of iodine are poured over with 200 ml of cyclohexane.

The suspension is boiled for I ¹ / * hours under reflux with stirring, are again 5 g N-iodosuccinimide and further to cooking IV reflux for ₂ hours. As indicated in Example 18, the suspension is worked up and purified. After chromatographic separation, 1.53 g of 3 / ?, 17/9-diacetoxy-6 / J, 19-oxido-androstane with a melting point of 144 ° to 146 ° are obtained.

Claims (7)

Patent claims: 1. A process for the preparation of 6 / ?, 19-oxidosteroids, characterized in that a 19-unsubstituted 6 /? - hydroxysteroid, which contains no further free hydroxyl group, is mixed with a monovalent, positive iodine-containing compound in an inert organic solvent, expediently at elevated temperature, treated and, if desired, the 6 / 3,19-oxidosteroid obtained in a manner known per se, before or after hydrolysis of any acyloxy groups present, esterification of hydroxy groups present and / or introduction of a lower alkyl, alkenyl or alkynyl radical into the 17λ position of a 6 / 3,19-oxido-17-oxoandrostane compound obtained or a hydroxyl group to the 17 "position of a 6 / 3,19-oxido-20-oxo-pregnane compound obtained, oxidized and optionally in a known manner Oxo groups present are reduced, hydroxyl groups present are dehydrated and / or a Δ ⁴ -3-oxo group is introduced. 2. The method according to claim 1, characterized in that there is used as a monovalent, positive iodine Compounds containing acylhypojodite are used. 3. The method according to claim 2, characterized in that the acyl hypojodite is an intermediate from lead tetraacylates, mercury acylates or Produces silver acylates and iodine directly in the reaction solution. 4. The method according to claim 1, characterized in that the implementation of the starting steroid in an alicyclic or halogenated hydrocarbon. 5. The method according to claim 1, characterized I 192 193 characterized in that one carries out the reaction of the starting steroid, at a temperature between 50 and 15O ⁰ C. 6. The method according to claim 1, characterized in that that the reaction solution containing the starting steroid with visible and / or irradiated with ultraviolet light. 7. The method according to claim 1, characterized in that the starting materials 5a> halogen 6 / J-bydroxysteroids, advantageously 3/5-acyloxy-5 "-halogen-6 / mydroxy compounds of the spirostane, androstane and pregnane series, in particular a 3ß - acyloxy - 5a - halogen - 6ß - hydroxy - spirostane, SjS-acyloxy Soi-halogen-ö / S-hydroxy-17-oxo-androstane, 3 / J, 1 'Z / S-diacyloxy-Soc-halogen-o / i-hydroxy-androstane, 3/3 - acyloxy - 5 <x - halogen - 6ß - hydroxy-20-oxo-pregnane or S / ^ na-diacyloxy-S
6 /? - hydroxy-20-oxo-pregnane, is used. 509 563/458 4.65 Q Bundesdruckerei Berlin