DE1192195B - Process for the production of 19 oxygenated z15 steroids - Google Patents

Description

UNDESREPUBLIC OF GERMANY

EUCHES

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

CO

? / 1 / h

German class: 12 ο - 2S /

Number: 1192195

File number: C 24474IV b / 12 ο

Filing date: June 28, 1961

Opening day: May 6, 1965

The invention relates to a new process for the production of 19-oxygenated <d ⁶ -steroids from 5 "-halogen-6, 19-oxido-steroids. The 19-oxygenated steroids obtained in this way are important intermediate products for the production of pharmacologically important 19-nor-steroids, e.g. B. of derivatives of 19-nor-testosterone and 19-nor-progesterone. In particular 19-nor-17-methyl-testosterone, 19-nor-17a-ethynyl-testosterone and certain esters of 19-nor-testosterone have recently found therapeutic use.

Until recently, in addition to total syntheses, three methods were known for the production of such 19-norsteroids. The most important, also used industrially, consists in the reduction of steroids with an aromatic ring A by an alkali metal in liquid ammonia. The microbiological hydroxylation of the C-19 methyl group of J ⁴ -3-oxosteroids, which is in view of the easy removability of oxygenated angular substituents "a" promising method is, however, severely limited by the substrate specificity of the enzyme systems Finally, the modification of turns. of oxygenated in position 19 natural products (z. B. strophanthidin) in therapeutically useful 19-nor-steroids * 5 because of the large number of required reaction steps as uneconomical. in contrast, the method of the present invention are in accordance with 19-oxygenated steroids Δ ⁶ from the 6 / J, 19-oxido-steroids, which are easily accessible according to the process of patent application C 24472 IVb / 12o, can be prepared in an extremely simple manner.They can be converted into the above-mentioned 19-norsteroids by known, likewise very simple methods.

The method according to the invention consists in that a 5 "-halogen-6 |?, 19-oxido-steroid with a Treating reducing agents in a manner known per se and, if desired, by known methods esterifies an obtained steroid 19-acid and / or hydrolyses an obtained steroid alcohol ester.

The starting materials can also have a Have a hydroxy or oxo group, d. That is, hemiacetals from 6 /? - hydroxy-19-oxo-steroids can also be used or 19,6 / S-lactones of 6/3-hydroxy-steroid-19-acids be used. In addition, the starting materials include spirostan-, androstan-, pregnan-, cholan-, Cholestan, Stigmastan and Cardanolide series and can be in the Tling system, especially in one or several of the positions 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 14, 15, 16, 17, 20 and 21, have further substituents, such as free or functionally modified oxo groups, esterified or etherified hydroxyl groups, alkyl (ζ. Β.

Process for the production of 19-oxygenated
zJ ³ steroids

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. JaroslavKalvoda, Basel;

Dr. Helmut Ueberwasser, Riehen (Switzerland)

Claimed priority:

Switzerland of July 15, 1960 (8133),

of October 28, 1960 (12 107),
of December 23, 1960 (14 393),
dated April 5, 1961 (3990),
dated June 2, 1961 (6481)

Methyl) groups and / or halogen atoms. Functionally modified oxo groups are ketalized or in enol derivatives, e.g. B. enol ethers or enol esters, converted oxo groups understood. aside from that the starting materials can also have double bonds or oxido groups, e.g. B. in 4,5-, 9.11 or 16.17 position.

Particularly important starting materials are those Sa-halogen-ö & ^ - epoxies which have a free, esterified or etherified hydroxyl group or a ketalized oxo group in 3-stelhmg, since then, following the reduction according to the process, a zJ ⁴ -3-oxo group can easily be obtained in a known manner can be introduced, which facilitates the cleavage of the angular C-19 substituent.

The 5a-halo-6jß, 19-oxido-steroids used as starting materials are in accordance with the processes of patent applications C 24 472, which are not claimed here and C 24473 IVb / 12o by the action of monovalent, positive iodine-containing compounds or from lead tetraacylates to 19-unsubstituted 5 ″ -halogen-6 / S-hydroxy steroids manufactured.

509 568/460

3 4

The above-mentioned, are also obtainable as starting materials by the process of the invention

usable hemiacetals of 6 / J-hydroxy-19-oxo- e.g. <d ^s -3,19-dihydroxy compounds of spirostane,

steroids or 19.6 / 3-lactones of the 6/3-hydroxy-steroid, androstane and pregnane series and esters thereof,

19-acids are oxidized by the last - in particular zl ⁶ -3,19-dihydroxy-spirostene, z. B.

thought they had received 6 / ?, 19-oxido steroids. 5 19 - hydroxy - diosgenin, Δ * - 3.17 / 3.19 - trihydroxy

Specific starting materials for the invention androstene, which in the 17 «position is an alkyl,

proper procedures are e.g. B. can have the following compounds alkenyl or alkynyl radical, z. B.

gen: 3 - hydroxy - 5 «- halogen- 6 / 3.19 - oxido - spirostane Δ ⁱ - 3ß, 17 / 3.19 - trihydroxy - androsten, Δ ⁶ - 3 / 3.1 Iß, 19-

and their esters, e.g. B. the Sß-acetoxy-SÄ-chloro-trihydroxy-17 «-alkyl-, especially -17« -methyl-

6 / ?, 19-oxido-spirostane, 3 / 3,17 / 3-dihydroxy-5α- chloro-xo androstene, -17 «-ethyl-androstene and -ha-isobutyl-

and -5 <x-bromo-6 / ?, 19-oxido-androstane and its esters, androsten, also J ⁶ -3 / 3,19-dihydroxy-pregnene,

the S / S-Hydroxy-Six-cblor- and -Sa-bromo-ö / S ^ -oxido- which in the 20-position is a free or ketalized one

17-oxo-androstane and its esters, ?> Ss, \ lß-O '\ hyAzoxy- oxo group, z. B. J ^B -3 / 3,19-dihydroxy-20-oxo-

5 <x-chloro- and -SÄ-bromo-o ^ W-oxido-niX-alkyl-, in particular, Zl ⁵ -3 / 3,17a, 19-trihydroxy-20-oxo-pregnen

special -Ha-methyl- and -Πα-ethyl-androstane and 15 or J ⁵ -3 / 3,17a, 19,21-tetrahydroxy-20-oxo-pregnen

its esters, 3/3, nβ-dihydroxy-sa-chloro and sa-bromo and esters thereof.

6 / 3,19-oxido-17iX-allyl-androstane and its esters, In addition, S / ^ O-dihydroxy-Sa-chloro- and -5tx-bxom-6ß, \ 9-oyado- can be produced by the process of the invention: zl ⁵ -3-Hydroxy-19-acids of Androstanpregnan and its esters, 3/3-Hydroxy-5'-chlorine and Pregnan series and esters thereof, in particular -5a-bromo-6 / 3,19-oxido-20- oxo-pregnane and its 20 19-acids of Δ ⁶ -3-hydroxy-androstenen, which in ester, 3jö-hydroxy-5ix-chloro and 5a-bromo-6 / 3,19-oxido 17-position a free or esterified hydroxyl group 16,17a-oxido-20-oxo-pregnane and its esters, and optionally an alkyl-, alkenyl- or 3 / 3,17α-dihydroxy-5'-chloro- and -5α-bromo-6 / 3,19 - Have an alkynyl radical or an oxo group, for example oxido-20-oxo-pregnane. In addition, 19-acids and esters thereof of Δ ⁵ -3 / ?, 17 / S-Di become 19.6 / S-lactones of 5 "-halogen-6 ^ -hydroxy-25 hydroxy-androstene, e.g. ^B -3 / 9-hydroxy-17-oxo-androstene, steroid-19-acids, which are derived from the corresponding J ⁶ -3j3,17 | 8-dihydroxy-17 "-alkyl-, in particular 17a-5 <x -halo-6 / ?, 19-oxido-steroids can be produced by oxidation of methyl-androstene, -17a-ethyl-androstene and -17a-iso. This can e.g. B. happen, butyl-androsten or corresponding 3-acylates or by the 6 / 3,19-epoxides with strong oxidation 3,17-diacylates, further 19-acids and esters of the same average, z. B. with ruthenium tetroxide or especially 30 of J ^s -3 /? - Hydroxy-pregnenen, which in the 20-position with derivatives of 6-valent chromium such as chromium a free or esterified hydroxyl group or an acid or tertiary butyl chromate, in solvents, free or have ketalized oxo group, e.g. B. lower fatty acids, such as acetic acid, propionic The in the starting materials and the process acid, or in chlorinated hydrocarbons, such as according to the products obtained, carbon tetrachloride ester, especially at elevated 35 groups are derived from saturated or unge temperature, such as between 50 and 100 ⁰ C treated. saturated aliphatic or cycloaliphatic, of

The 5'-halo-6 / 3,19-epoxides are opposite to aromatic or heterocyclic carboxylic acids

hydrolytic agents very stable. Surprisingly or from amino acids.

wisely, however, the opening of the 6 / 3.19-oxygen- 19-acid can bridge obtained according to the method is successful easily under reductive conditions, inside in a manner known per se into corresponding esters, special with such reducing agents, which z. B. with diazomethane or diazoethane, in the entfür the reduction of halohydrins to olefins-speaking methyl or ethyl esters converted can be used. Are particularly suitable. Obtained steroid alcohol esters can also be metallic Reducing agents, such as alkali or earth case, are hydrolyzed according to known methods, alkali metals such as sodium, potassium, lithium or be 45 The following examples explain what is particularly special to the invention Calcium, especially dissolved in liquid according to the method. The temperatures are in Celsius ammonia or an amine such as ethylamine, isogrades given, propylamine or ethylenediamine, optionally under _. . . . Addition of a diluent such as ether, tetra example hydrofuran or dioxane. 50 In a four-necked flask with stirrer, gas inlet

Under the specified reaction conditions tube, dropping funnel and reflux condenser, which is equipped with a

J ⁵ -19-hydroxy steroids are formed. At the same time with moisture protection and a gas discharge pipe

the reductive opening of the 6 / 3,19-epoxides can be provided, 100 ml of ammonia are condensed

other functional groups such as other epoxy (bath temperature-60 °). In portions it is now 1.00 g

groups, e.g. B. 16,17-epoxides, or oxo groups, if 55 lithium metal is added, which is in the ammonia with

it does not dissolve blue color by ketalization or enol ether formation, and then with stirring

are protected, are also reduced. in quick succession a solution of 3.00 g 3 /? - acetoxy-

Bd the ^, oß-hemiacetals of 5 * -halogen- 5% - chloro-6 / 3,19-oxido-cholestane in 50 ml of absolute 6 / S-hydroxy-19-oxo-steroids and especially ether added dropwise. After removing the cooling from the 19,6 ^ -lactones of the 5a-halogen-6 / S-hydroxy- 60 bath, while stirring and passing over a dry steroid-19-acids, the reductive opening succeeds outside of a nitrogen stream within 2 hours of the ammo with the abovementioned Reducing agents also evaporated under niac, whereby at intervals of tired conditions, especially with zinc and 20 minutes each 25 ml of absolute ether is added, a lower alcohol such as methanol, ethanol, the superfluous lithium is destroyed with methanol, and particularly smooth with propanol Zinc and a 65 and the reaction mixture after acidification with lower fatty acid, such as acetic acid or propionic acid. dilute sulfuric acid and dilution with ether. The 5-halogen-19.6 /? - lactones are well worked up. The successively with water, sodium yield J ⁵ -steroid-19-acids. bicarbonate solution and water washed and

Ethereal solution dried with sodium sulphate, by suctioning off excess zinc, concentrating after evaporation in vacuo, 2.52 g of an oily filtrate in vacuo, taking up the return product, which crystallizes in chloroform when sprayed with methanol, washing the chloroform. After recrystallizing once from methylene solution with 2 η-sulfuric acid, then with water, chloride-methanol, 1.130 g of ⁸ -3 /? Hydroxy-cholesterol) in the form of colorless crystals which, from methanol-ether, have a temperature of 153 to 155 °. The IR spectrum shows, among other things, redissolved, characteristic absorption bands at 252 to 253 ° without evolution of gas at 2,80,6,86, melting.

7.30, 7.36, 7.50, 9.25, 9.70, 9.85, 10.30, 10.48, 10.87, by treating this acid dissolved in chlorol, 30 and 11.90 µ. ίο form, with essential diazomethane solution at Raura-

From the nuclear magnetic resonance spectrum, the maximum temperature is missing for a few minutes

of the C-19 methyl group, whereas at 153 to /! '' - S ^ -Acetoxy-n-oxo-androstene - ^ - acid-methyl-

184Hz and 45 to 48.5Hz maxima, which the ester, which, redissolved from ether, at 188 to 189 °

Protons that melt.

i 15 1.7 g J ⁸ -3 /? - Acetoxy-17-oxo-androstene-19-acid-

- CH.-OH- or. the - C = CH grouping methyl ester are dissolved in 200 ml of methanol, in

a nitrogen atmosphere with a solution of 2 g

can be assigned. Potassium carbonate is added in 10 ml of water and 1 hour

In an analogous manner, 5.0 g of 30-acetoxy are obtained which are boiled with stirring. After cooling, it will

5 «-chlor-6 / ?, 19-oxido-spirostane 3.6 g of 19-hydroxy-ao reaction mixture strongly concentrated in vacuo and

diosgenin, which bands at 2.78 in the IR spectrum, then extracted with chloroform. The chloroform

7.30, 9.52, 9.85, 9.92, 10.20 and 10.40 µ. solution is dried and evaporated. You get

. 1.5 g Δ ⁶ -3ß- hydroxy-17-oxo-androstene-19-acid

Example 2 methyl ester, obtained from isopropanol in crystals

In 100 ml of liquid ammonia, the temperature from 188 to 190 ° is separated out at rest,
Ren at -60 ° 750 mg lithium metal in portions. .
dissolved. 1.00 g of B e ι s ρ ι e 1 4 are added to the blue solution
SjS-Acetoxy-Sa-chloro-o / JW-oxido-n-oxo-androstane The condensation is carried out in a 500 ml stirred flask and rinsed with 50 ml of absolute ether. Under 200 ml of ammonia and then add 1.5 g of stirring, without external cooling, then 30 lithium metal is added in small portions. The blue solution, which has remained in a stream of dry nitrogen for 1.5 hours, is allowed to pass over the reaction solution over a period of 15 ml, and the removed 1.95 g of S / I ^ O / i-diacetoxy-chloro / Il ^ -oxidodampfte ammonia replaced by absolute ether. Add pregnane in 20 ml of tetrahydrofuran dropwise and the excess lithium is finally decomposed by means of stirring for a further 1.5 hours. Then methanol is added and the mixture is slowly allowed to stand for 18 hours at 35 a mixture of 20 ml of methanol and room temperature. After acidifying the Re 100 ml of ether and finally lets the ammonia action mixture with dilute sulfuric acid and evaporate. Finally, a further 100 ml of extraction by means of chloroform are added, 857 mg of a tetrahydrofuran are added, and nitrogen oil is isolated over the course of 1 hour. This crystallizes when sprayed with through the suspension, diluted with 200 ml of water, ethyl acetate-ether. The Zl ⁶ -3 / S, 19,17-tri-40 is obtained in this way and extracted several times with methylene chloride. The hydroxy-androsten from 231 to 233 °. Extracts are made with dilute sulfuric acid and _. · 1, washed with water, dried and evaporated. Example J _{Man erMU lg2g raw} j ^^ OjS-Trihydroxy-

To prepare the starting material, 5 g pregnen with a melting point of 225 to 227 ° (from methylene chloride -

S / S-Acetoxy-Sa-chloro-öjS. ^ - oxido-n-oxo-androstane, 45 methanol-ether),
dissolved in 100 ml of glacial acetic acid, at 85 to 90 ° in the course of

30 minutes with a solution of 7.5 g of chromium trioxide Example 5

added in 7.5 ml of water and 60 ml of glacial acetic acid. After a solution of 1.0 g of 3 /? - Acetoxy-5a> bromine-

A further 15 minutes reaction time is diluted with 6 / 3,19-oxido-17-oxo-androstane in 30 ml of glacial acetic acid

Water and extracted with methylene chloride. The 50 one 3.0 g of zinc dust and stir the reaction mixture Methylene chloride solution is with water, then with 12 hours at 100 °. It is then cooled and filtered Washed sodium hydrogen carbonate solution, then with the unused zinc and diluted the filtrate Dried sodium sulfate and evaporated. One er with methylene chloride. The solution will eventually holds 2.2 g lactone of S / S-Acetoxy-Sa-chloro-o / S-hydroxy- with water, dilute sodium bicarbonate solution

n-oxo-androstane - ^ - acid, which was washed by adding 55 and water, dried and evaporated. Ether crystallizes and redissolving from alcohol gives 897 mg of J ^B -3 / S, 19-diacetoxy-17-oxo is freed from still adhering oxido compound. androsten, which crystallizes from methanol — water. The pure compound melts at 198 to 199 °. siert, melts at 103 to 105 "; [a] f? = -39.6 ° (in 2.0 g of the chloroform used as the starting compound), IR bands at 5.75, among others,

19.6 / 3-lactones of the 3 /? - acetoxy-5 «-chlor-6 /? - hydroxy-60 5.76, 8.15 and 9.73 μ.
17-oxo-androstane-19-acid are made with an off. .

100 g zinc dust by washing with 1 η-acetic acid, B e ι s ρ 1 e 1 6

then paste of active zinc prepared with glacial acetic acid, 2.5 g S / ^ n / J-Diacetoxy-Sa-brom-o / S. ^ - oxido-an-

which to improve the stirrability further drostan are dissolved in 75 ml of glacial acetic acid. To this

40 ml of glacial acetic acid are added, 10.0 g of zinc dust are added over 2 hours and the mixture is stirred and refluxed. After this mixture 10 hours at 100 °. It is then cooled, it is time for the above lactone to convert to the unused zinc being filtered off and the zJ ⁵ -3 / 3-acetoxy-17-oxo-androstened-19-acid is completely evaporated. Filtrate in a water jet vacuum. You take that

Residue in methylene chloride and water, the organic solution washes neutral, dried and evaporated. The residue (1.97 g), which contains the zJ ⁶ -3 / ?, 17 / 5,19-triacetoxy-androstene, is dissolved in 100 ml of methanol and, after addition of 2.5 g of potassium carbonate, heated in 10 ml of water the mixture is boiled for 3 hours. Then 3.5 ml of glacial acetic acid are added, the solution is concentrated to about 50 ml in a water jet vacuum, extracted with a methylene chloride-methanol (5: 1) mixture, the extracts are washed with water, dried and evaporated . Crystallization of the residue from ethyl acetate ether gives 1.35 g of pure Δ ⁵ -3β, Πβ, 19-Ίή- hydroxy-androstene with a temperature of 231 to 233 ".

Claims (4)

Patent claims: 1. A process for the preparation of 19-oxygenated J ⁶ steroids, characterized in that a 5a-halo-6 / 5,19-oxido-steroid is used with a reducing agent known per se Treated manner and, if desired, a steroid 19-acid obtained by known methods esterified and / or hydrolyzed a steroid alcohol ester obtained. 2. The method according to claim 1, characterized in that the starting materials are those 5 «-halogen-6jÖ, 19-oxido-steroids used in 19-position) have an oxo group and advantageously an esterified hydroxyl group in the 3-position. 3. The method according to claim 1, characterized in that the 5a-halogen-6 / ?, 19-oxidosteroid treated with an alkali metal in liquid ammonia. 4. The method according to claim 1, characterized in that 6 / S, 19-lactones of 5 <x-halogen-6 /? - hydroxy-steroid-19-acids treated with zinc and a lower fatty acid. Considered publications:
Joura. Chem. Soc, 1957, pp. 4604-4608.