US2397424A - Process of preparing sex hormones - Google Patents

Description

Patented M... 26, 1946 UNITED I STATES; PATENT OFFICE PROCESS OF PREPARING SEX HORMONES Russell Earl Marker, State College, Pa., and Eugene L. Wittle, Detroit, Mir-.11., assignors to No Drawing.

Parke, Davis 8: Company, Detroit, Mieln, a corporation of Michigan Application October 25, .1940, Serial No. 362,836

27 Claims. (Cl. 260-3973) sex hormones can be prepared from sterols or bile acids in improved yields.

Another object of this invention is to afiord a simplified process for the preparation of compounds simply convertible into sex hormones.

Yet another object of this invention is to ailord a new process for the preparation of A -3-keto steroids such as the sex hormones from A -unsaturated steroids.

Other objects will become apparent on perusal of this specification and the appended claims.

In the. past, steroidal sex hormone intermediates, i. e., compounds of the androstane and pregnane series, have been prepared by protecting the C3 hydroxyl and the A double bond of sterols such as cholesterol, cinchol, sitosterol and other sterols, and then oxidatively removing all or the greater portion of the side-chain attached to C11. Because of the instability and sensitivity of the dihalides of esters of sterols, this process does not give very satisfactory yields. In order to obtain the best results, the conditions of oxidation must be carefully controlled and even under these conditions it is diflicult to recover a reasonable amount of the unreacted starting material. Onthe other hand, the oxidation of sterol derivatives which are more stable than the dihalides oi the esters of sterols gives better yields, but now it be.- comes more diillcult to convert the sex hormone intermediates so formed into the sex hormones. themselves. For example, while the oxidation of the acetate of coprostanol proceeds reasonably satisfactorily, the subsequent conversion of the androstane and pregnane compounds thus obtained into sex hormones requires numerous steps with a very low overall yield.

We have set ourselves to the problem of improving the yields in the preparation of sex hormones iromsterols and bile acids and to this end have succeeded in developing a process in which the step of oxidation proceeds in good yields to -Our process consists essentially in treating a steroid 01 the formula,

CH: CH:

where R is a member of the group consisting of hydrocarbon radicals and oxygenated hydrocarbon radicals, X is a halogen, and one of Y and Z is a member of the group consisting of hydrogen and halogen, the other being hydrogen, with an agent'capable of oxidatively rupturing carbon-tocarbon bonds of the group'R, treating the oxidation products having a shortened side-chain thus obtained to obtain the corresponding A -unsaturated steroids, and treating these with an agent capable of oxidizing a methylene group adjacent to a double bond thus forming the corresponding 3-keto zi -unsaturated steroids having a shortened side-chain.

In greater detail, our new process consists first in forming a A*-' or A -unsaturated sterol or bile acid derivative. Because of their availability, we prefer to use as starting materials, the naturally occurring sterols in which the side-chain R is a hydrocarbon radical containing 8 to 10 carbon atoms. This side'chain may be saturated, as in cholesterol CaHrz or sitosterol C1oH21, or it may be unsaturated as .in ergosterol CcHr'i. sterols of this type are readily converted into the corresponding 3-desoxy compounds, i. e. into the A or A -unsaturated hydrocarbons. may be distilled at atmospheric pressure to give A -cholestene, or it may be treated with phosphorous pentachloride or thionyl chloride to form cholesteryl chloride, and the latter reduced as for example with sodium and amyl alcohol to yield A -cholestene.

The A4 or A -unsaturated steroidal hydrocarbon used as a starting material is first treated with halogen or hydrohalic acid to add the elements of these substances to the steroidal double bond. We prefer to use chlorine, bromine, hydrogen Thus cholesterol chloride or hydrogen bromide in this step. The

compound thus obtained has a halogen atom attached to C and another halogen atom or hydrogen atom, depending upon whether halogen or hydrohalic acid was added, is attached to the other carbon atom of the original double bond. The dihalide or hydrohalide addition product thus obtained is then oxidized under conditions sufficiently vigorous to rupture'carbon-to-carbon bonds. While a variety of a en s may be employed for this purpose, we prefer to use chromic acid, permanganic acid or their salts and we find it most convenient to conduct the oxidation in acetic acid below 100 C. and preferably at 35- Suitable dehalogenating a ents include sodium iodide, zinc and acetic ac d. meta lic ma nesium. and the like. and suitable deh dronaloeenating agents are basic substances such as 'ovridine. sodium acetate and ot er alkali metal salts of carboxvlic'acids. and the like.

our new method for the preparation of M-unsaturated 3-keto steroids from A -unsaturated steroids. This method consists in oxidizing to a ketone group a methylene group adjacent to a double bond and this oxidation is effected by first protecting any hydroxyl groups by convertin these into derivatives such as acetates,- benzoates, trityl ethers or other groups hydrolyzable to give OH and oxidizing the derivative thus obtained with an agent capable of converting into a ketone group a methylene group adjacent to a double bond. Such agents include chromic acid and permanganic acid and their salts, as well as selenium dioxide. The conditions of reaction depend on the particular oxidizing agent employed, e. g. we prefer to use chromic acid in acetic acid at -60 C.

The selectivereduction of M-androstenone-l'i may be accomplished with a wide variety of reducing agents. Theseinclude catalytic hydrogenation with a Raney nickel catalyst, andthe If a M-unsaturated steroid has been used as a starting material or if hvdro en halide. was the agent added to the unsaturated ste o d (either A or AP). then the roduct formed after removal of the elements of halo en or hvdrohalic acid. as the casemaybe. is a M-u'nsaturated compound. If; however. the dihalide of a A -unsaturated steroid was the substa ce oxidized. after removal of the elements of halo en the product obtained is a [i -unsaturat d steroid and it is necessary at some point in the rocess to convert this intoa M-unsaturated steroid. This is-done by adding and then removing the elements of hydrohalic acid.

. This shi ting of the double bond from Alto A in the oxidation products may be carried out at any stage after the unreacted starting material has been removed from the oxidation products but it-must. of course. be done before the steroid is a ain oxidized to form the 3-keto steroid as double bond in the A-' -position. may be converted into the corresponding A -androstenone-l7.

The M-androstenone-IT thus obtained may be oxidized according to our new method to form A -androstendione-3J7 and the latter selectively reduced to form Ai-androstenol-1'7-one-3 (testosterone).

Otherwise the M-androstenone-i'l mav first be selectively reduced under conditions which leave a doublebond unaltered so as to form A- androstenol-l7, the hydroxyl group of the latter rotected bv conversion into a derivative hydrolyzable to regenerate A -androstenol-17 and this derivative oxidized according to our new method to form the corresponding derivative 0! a a dr0steno1-1'7-one-3.

combination of an alkali or alkaline earth metal or aluminum and asubstance having reactive hydrogen atoms. Reducing agents of the latter class include such combinations as sodium and ethyl alcohol, aluminum amalgam and aqueous ammonium chloride, calciumand methanol, and the like. Instead of these the reduction may be conducted according to the method or Meerwe'in and Ponndorfi. using, for example, ammonium isopropylate and isopropyl alcohol.

It will be appreciated that our invention also comprehends a new group of intermediates for the preparation of sex hormones. This new group of substances is representable by the generalformula CH1 CH3 where Q is a member of the class consisting of (=0) groups hydrolyzable to =0),

and groups hydrolyzable to This group of substances includes N-androstenone-17, its semicarbazone, its oxime, A -androstenol-l"! and its esters such as its benzoate, acetate, furoate and butyrate.

Our invention may be more fully illustrated by the following examples:

Example 1 (a) In a 12 liter flask is placed 230 g. of A cholestene dibromide prepared, e. g., according to Mauthner, Monatsch. 27, 421 (1906), and 500cc. of carbon tetrachloride. When solution is complete, 8 liters of glacial acetic acid are added and the solution warmed to 45 C. with stirring. To this stirred solution at 48-50 C. is added dropwise a stirred solution of 320 g. of chromic anhydride in 350 cc. of water and 800 cc. ofacetic acid over a period of four or live hours. .The solution In either case the process involves the use of is stirred at 50 C. for six hours longer and, then cooled with cold water or ice to 30 C. Then ethyl alcohol (250 cc.) is added slowly to this stirred solution over a period of about one-hall hour to destroy any excess chromic anhydride. The acetic acid is then removed under reduced pressure until the volume of the solution has been reduced about one-half. During the evaporation the temperature of the solution is kept at.40-45 C. The so- .lution is cooled slightly and the unchanged dibromide filtered oii and dried. The filtrate is further concentrated under reduced pressure at 40 C. until only a small quantity of acetic acid remains. This residue is diluted with 4 liters of water and 2.5 liters of ether'and stirred until all the material is in solution. The water layer is separated and extracted with 2.5 liters of ether. The combined ethereal extracts are washed well with 2 liters of water, 3 liters of water containing 300 cc. of conc. hydrochloric acid, and then twice with 1.5 liters of salt water, sumcient salt being added to cause rapid separation of the layers. The ethereal solution then is evaporated to dryness. the last ether being taken oil cautiously to avoid undue heat. The residue contains the di- -bromides of A -androstenone-l7, A -pregnenone- 20, and A -cholenic acid.

Instead of using A -cholestene dibromide in the above step, A -cholestene dichloride, n -sitostene dibromide, A -sitostene dichloride, or other dihalides of A -unsaturated hydrocarbons derived from sterols may be used instead.

(b) One liter of acetic acid and 5 g. of zinc dust is added to this residue and the solution stirred vigorously and heated to .95 C. on the steam bath. A further 45 g. of zinc dust is added to this stirred solution in small ortions over a period of forty-five minutes. Then the solution is filtered from the caked zinc and the latter washed well with acetic acid. The acetic acid filtrate is evaporated to dryness in vacuo on the steam bath and the residue dissolved in 2 liters of ether. The ethereal solution is washed twice with water and the acid fraction is extracted with 5% sodium hydroxide solution until all acids are removed.

(0) The ethereal solution is evaporated to dryness and the residue steam distilled to remove the volatile products. The' residue is dissolved in ether and the water layer removed. After evaporating the ether, the residue is dissolved in 200 cc. of 95% ethyl alcohol. Five grams of semicarbazide hydrochloride and 6 g. of sodium acetate are added and the mixture refluxed on the steam bath for four hours, the alcohol being allowed to" evaporate to one half volume. The solution is cooled and diluted with 500 cc. of ether. After shaking the suspension for about one-half hour with cooling, 200 cc. of water is added. The solution is shaken and cooled in a salt-ice bath and then filtered with suction. The white solid is washed well with water and ether. Then it is refluxed with 50 cc. of alcohol for one hour, cooled, flltered, and air dried; yield 5 g. of white powdered semicarbazone, M. P. 285-287 C. This is the semicarbazone oi. A -androstenone-17.

(d) A solution of 6.7 g. of M-androstenone-fl semicarbazone, in 500 cc. of 95% ethyl alcohol, 35 cc. of concentrated sulphuric acid and.35 cc. of water is refluxed for two and one-half hours on the steam bath. The solution is diluted with water and the organic material extracted with ether. The ethereal solution is washed well with water and sodium bicarbonate solution and evaporated to dryness. The residue is purified by distillation at 80 C. in a molecular still and crystallization from dilute alcohol to yield a c. or A -androstenone-17, M. P. 100-105 C. On further purification the M. P. may be raised to 105-107" C.

(e) To a solution of 1.7 g. of M-androstenone- 17 in 26 cc. of refluxing n-propyl alcohol is added 2.5 g. of sodium in small portions over a period of a half hour. Then the solution is poured into water and the white solid collected. This is crystalized from methanol to yield 1.4 g. of A -androstenol-l'l, M. P. 163-165 C.

Three grams of A -androstenol-17 is refluxed for one hour with 30 cc. acetic anhydride and then the solution is evaporated'to dryness under reduced pressure. The residue is dissolved in hot methanol and allowed to crystallize, The A -androstenoi-lT-acetate thus formed has M. P. 133-135 C. Hydrolysis of this acetate, e. g., with alcoholic potassium hydroxide, regenerates the original hydroxy compound, A -androstenol-17.

(j) A stream of dry hydrogen chloride is bubbled for several hours through a-solution of 1 g. of M-androstenol-l'? in about 20 cc. of chloroform. cooled to 0 C. After the cold solution has stood for several hours, it is carefully evaporated to dryness under reduced pressure on a water bath. The white solid hydrochloride remaining behind is dissolved in ethyl alcohol and refluxed for six- -A mixture of these two acetates gives a depression in melting point to 72-82 C.

A solution of 500 mg. ofn -androstenol-l7 acetate. M. P. 97-100" C. in 25 cc. of methanol is refluxed for a half hour with a solution of 1 g. of

potassium hydroxide in 10 cc. of 50% methanol. The solution is diluted with water and extracted with ether. The ethereal solution is washed with water and evaporated to dryness. The A -androstenol-17 is purified by crystallization from methanol, and then has M. P. l46-l49 C.

To a solution of 200 mg. of A -androstenol-17 in 100 cc. of acetic acid is added 0.73 cc. of 1.05 molar bromine in acetic acid. After a few'minutes, a solution of 300 mg. of chromic anhydride in 20 cc. of 90% acetic acid is added with shaking. The solution is allowed to stand at room temperature for one hour and then warmed with five grams of zinc dust on the steam bath. The solution is filtered, poured into water and the product extracted with ether. The ethereal solution is washed well with water and dilute'alkali and evaporated to dryness. The residue is distilled in a molecular still under reduced pressure and then crystallized from dilute methanol to give M-androstenone-17 of M. P. 78-80 C. This ketone gives a depression in melting point to 60-65 C. when mixed with A -androstenone-17.

(y) To a solution of 2 g. of A -androstenol-17 acetate in cc. of glacial acetic at 50 C. is added a solution of 2 g. of chromic anhydridein 25 cc. of acetic acid over a period of one hour. The solution ispoured into water and extracted with ether. The ethereal solution is washed well with water and dilute sodium carbonate solution and then evaporated to dryness. The resulting oil, which shows a high androgenic activity, is treated in the known manner with Girards reagent I to separate the ketonic fraction. The

- crude ketone is hydrolyzed by warming with alcoholic hydrochloric acid and then distilled in a molecular still at 0.01 mm. pressure. Crystallization. of the product so obtained from ether-pens tens or dilute methanol gives testosterone, M P.

1 148-.150 0., identical with the natural product.

' Example 2 (a) A -Androstenol-1'l is prepared, e. g.. as dey scribed in Example 1 (f) (b) To a solution of 2.5 g. of M-androstenoll'l in 200 cc.-of acetic acid is added at -45 C. and

with stirring, a solution of 3g. of chromic anhydride in 5000. of 90% acetic acid. The addition requires one-half hour and the solution is thenkept at C. for another half hour. The solution is poured into water and extracted with ether.

The ethereal layer is washed well with sodium carbonate solution and water and concentrated to a small volume. 'On cooling this solution for some time crystals form and are 001..

and dissolved in cc, of acetic lution. at 45 C., thereis added a solution 011.5 g. V

of chromic anhydride in 20 cc. of 90% acetic acid [over a period of a half hour. The'mixture is small volume, and rendered cloudy by the addition of ligroin. On standing, crystals of A -androstenedione-3,17 separate. After recrystallization, this product melts at 170. The mother liquor from the separation of the M-androstenelected. They may be recrystallized from ether to yield A -androstenedione-3, 17, M. P,, 168-1'70 C.,

identical with the known substance.

Example 3 Y acid are stirred and maintained at 50 C. while a solution of 150 g. of calcium permanganate in 600 cc. of water, 100 cc, of sulfuric acid, and 2 l. of

acetic acid is added over a period of four hours. The mixture is stirred four hours more at 50 0..

dione-3,17'is made slightly turbid with ligroin' and filtered. through a column of alumina. The filtrate is evaporated and yields, after crystallize tion from dilute acetone, progesterone of M. P. 122 C.

Example 4 (a) M-Cholestene is prepared by the method of Heilbron and Sexton, J. Chem. Soc.

and then sulfurdioxide passed into the solution by filtration. The filtrate, consisting of an ethereal and an aqueous phase, is set aside for later treatment as described under ((1) below.

(c) The sparingly soluble sodium salt is suspended in water, and the suspension acidified strongly. Thismixture is well extracted with ether and the latter washed and'evaporated. The residue is crystallized from slightly diluted acetic acid and thus yields A -cholenic acid of M, P. 160 C. i

(d) The ethereal layer in the filtrate is separated and washed well with sodium hydroxide solution and water. After removing the ether on a steam bath, the residue is heated with 200 cc. of acetone, some methanol added, and the mixture chilled. The crude n -cholestene which separates is collected and recrystallized. The combined l a fraction collected at 7o-110 c. This is fractionally crystallized from dilute methanol and thus yields. M-androstenone-l'l of M, P. '78 80 C.

(e) The combined mother liquors from the above described crystallization of M-androstenone-17 contains M-androstenone-l'? and A pregnenone-ZO, and are evaporated to dryness (b). To 100 g. of A -cholestene in 500 cc..oi

carbon tetrachloride is added a 30% solution of.

bromine in carbon tetrachloride until the double bondis saturated with bromine. Then the mixture is warmed to 50C., 2 1. of acetic acid add ed, and a solution of 100 g. of chromic anhydride in 1 liter of acetic acid at 50 C, over a period of four hours. After stirring for four hours more at-this temperature, 150 g. of zinc dust is added, in small portions, and the mixture allowed to standovernight. the solution is decanted from the sludge, and concentrated in vacuo. The residue is dissolved in waterand ether, the layers separated, and the ethereal layer washed with sodium hydroxide solution. The ethereal extract is then evaporated to dryness, and the ketones removed from the residue in the known manner as the semi-carbazones. After hydrolysis of the purified semicarbazone, A -androstenone-1'7 of M. P. 79 C.- is obtained.

(c) To 1.5 g. of n -androstenone-l'l in cc. of acetic acid at 40 C. there is added slowly over a period of an hour, a solution of 1.5 g. of potassium permanganate in 20 cc. of water and 50 cc. of acetic acid. After standing for an additional hour, the mixture is saturated with sulfur dioxide, concentrated to a smallvolume, and diluted with water. This mixture is extracted with ether and the ethereal layer washed with alkali and water and evaporatedto dryness. The residue yields, after crystallization from ether-pen,- tane, A andrdstenedione-Sd'? of M. P. 168-'l0 C.

7 Example 5 (a) A -Pregnenone-20, M. P. -C., may be isolated from the mother liquors of the preparation of A -androstenone-1'7 as in Example 3, (d),or it may be prepared from M-pregnenol- 3(5) -one-20 by the steps of treatment with phosphorus pentachloride to obtain A -3-chloropregnenone-20, treating this with sodium and amyl alcohol to obtain A -pregnenol-20(a), and treating this as in Example 1, to obtain M-preg'nev none-20.

(b) To a solution of 2 g. of A -pregnenone-20 in 30 cc. of acetic acid at 45 C. is added over acid. 'rotmwi distillin cholesterol at atmospheric pressure according to The next day The residual sirup is dissolved in ether, shaken out with sodium hydroxide and water, and the ethereal extract evaporated. The residue is sublimed in a high vacuum and then crystallized from dilute acetone and thus gives progesterone melting at 120 C.

The above examples are intended to illustrate but not to limit the scope or our invention. Other modes oi employing our process apparent to those skilled in the art after this disclosure, are intended to fall within the scope of our invention and accordingly we wish to limit the scope of our invention only as indicated in the ap nded claims.

What we claim as or invention is:

1. The process which comprises treating a steroid of the formula,

CH: CH;

where R is a memberof the group consisting of hydrocarbon radicals and oxygenated hydrocarbon radicals, X is a. halogen, and one or Y and Z is a member or the group consisting of hydrogen and halogen, the other being hydrogen, with an agent capable of oxidatively rupturing carbon-to-carbon bonds, treating the oxidation products having a shortened side-chain thus obtained to obtain the corresponding M-unsaturated steroids, said treatment being determined by the nature of Y and Z, so that when Y is-halogen and Z is hydrogen, the treatment comprises the step of reacting the oxidation products with a dehalogenating agent, when Y and Z are both hydrogen the treatment comprises the step of reacting the oxidation products with a dehydrohalogenating agent, and when Y is hydrogen and CH: CH:

where R represents a sterol-side chain contain- 1 18 8 to carbon atoms, and X is selected from the class consisting of chlorine and bromide with an oxidizing agent selected from the class consisting of chromic acid, permanganic acid, and

their salts, treating the oxidation products thus obtained with a dehalogenating agent, isolating the A -androsten0ne-17 thus formed-converting pounds of hexavalent chromium, compounds of heptav-alent manganese, and selenium dioxide, and separating the 3-keto-A -androstenol- 1! compound thus produced.

3. The process which comprises treating a steroid of the formula,

CH: CH:

I where R represents a sterol-side chain containing 8 to 10 carbon atoms, and X is selected from the class consisting of chlorine and bromine with an oxidizing agent selected from the class consisting of chromic acid, permanganic acid, and their salts, treating the oxidation products thus obtained with a dehalogenating agent, isolating the A -androstenone-l'? thus formed, reducing to a carbinol group the ketone group of said A*- androstenone-17 under conditions which leave double bonds unaltered, protecting the C11 hydroxyl group by conversioninto a derivative hydrolyzable to regenerate the Cr: hydroxyl group, treating said derivative of M-androstenol-l'l with an oxidizing agent capable of oxidizing to a ketone group a methylene group adjacent to a double bond, said oxidizing agent being selected from the group consisting of compounds of hexavalent chromium, compounds of heptavalent manganese, and selenium dioxide, and separating the 3-keto- A -androstenol-17 compound thus produced.

4. The process which comprises treating a steroid of the formula, I

where It represents asterol-side chain containing 8 to 10 carbon atoms, and X is selected from the class consisting-of chlorine and bromine with an oxidizing agent selected irom the class consisting of chromic acid, permanganic acid, and their salts, treating the oxidation products thus obtained with a dehydrohalogenating agent, isolating the A -androstenone-ll thus formed, reducing to a carbinol group the ketone group of said A-androstenone-l7 under conditions which leave doublebonds unaltered, protectingthe 011 by droxyl group by conversion into a derivative 1W- drolyzable to regenerate the C11 hydroxyl group.

treating said derivative of A -androstenol-1'1 with an oxidizing agent capable of oxidizing to a ketone group a methylene 'group adjacent to a double bond, said oxidizing agent being selected from the group consisting of compounds of hexavalent chromium, compounds of heptavalent manganese, and selenium dioxide, and separating the 3-keto-A -androstenol-17 compound thus produced.

5. The process which comprises treating a steroid of the formula,

CH: CH:

, the C11 hydroxyl group by conversion into a derivative hydrolyzable to regenerate the Cr: hydroxyl group, treating said derivative of n -androstenol- 17 with an oxidizing agent capable of oxidizing to a ketone group a methylene group adjacent to a double bond, said oxidizing agent being selected from the group consisting 01 compounds of hexavalent chromium, compounds 01' heptavalent manganese, and selenium dioxide, and separating the 3-keto-A -androstenol-1'I compound'thus produced.

6. The process which comprises treating 5,6-

.dibromocholestane with an excess of chromic acid in acetic acid at 35-60 0., treating the oxidation products thus obtained with zinc dust, isolating the M-androstenone-l'l thus formed, reducing to a carbinol group the ketone group of said A -androstenone-17 with a reducing agent I selected from the class consisting of, (a) metals more electropositive than zinc in combination with a substance having reactive hydrogen atoms, (b) molecular hydrogen and a nickel catalyst, and the combinationof an aluminum' alcoholate and a secondary alcohol, converting the 'A -androstenol-17 thus formed into A -androstenol-17 by addition and subsequent removal of an agent selected from class consisting of hydrogen chloride and hydrogen bromide, acylating the C11 hydroxyl group to form 17-acyloxy-A -androstene, treating said 17-acylqxy-A -androstene with chromic acid in acetic acid at30-60" C. and separating the 17-acyloxy-M-androstenone-ii thus produced. 4

7. The process which comprises treating 5- chloro cholestane with an excess of chromic acid in acetic acid at 35-60 C., treating the oxidation products thus obtained with an valkali metal salt of an organic acid, isolating the A -androstenone-l7 thus formed, reducing to a carbinol group the ketone group of said A -androstenone- 17 with a reducing agent selected from the class consisting of, (a) metals more electropositive than zinc in combination with a substance having reactive hydrogen'atoms, (b) molecular hydrogen and a nickel catalyst,-and (0) the combination of an aluminum alcoholate and a secondary alcohol, acylating the C11 hydroxyl group'of the A -androstenol-l7 thus formed, treating said l7-acyloxy-A -androstene with chromic acid in acetic acid at -60 C. and separating the 17- acyloxy-A -androstenone-3 thus produced,

8. The step which comprises reducing A -androstenone-l'l with a reagent selected from the class consisting 0!, (a) metals more electropositive than zinc in combination with a substance having reactive hydrogen atoms, (b) molecular hydrogen and a nickel catalyst, and (c) the combination of an aluminum alcoholate anda secondary alcohol, to form M-androstenol-l'l.

9. The step which comprises treating an ester of M-androstenol-l'? with chromic acid in acetic acid at 30-60 0., thus forming an ester 01' A androstenol-l7-one-3.

10. A -Androstenol-l7-acetate of melting oint approximately 97-100 C.

11. An ester of the formula CH: CH:

where R is the acyl radical of a lower aliphatic carboxylic acid.

12. The processwhich comprises subjecting a steroidoftheformula,

CH; CH3

where R is a sterol-side chain'containing 8 to 10 carbon atoms and X is selected from the class consisting of chlorine and bromine, to oxidative side chain degradation by treatment with an oxidizing agent selected from the class consisting of chromic acid, permanganic acid, and their salts, treating the oxidation products thus obtained with a dehalogenating agent, converting the A unsaturated ketonic steroids thus obtained into the corresponding M-unsaturated steroids by addition thereto and subsequent removal therefrom of hydrohalic acid, and oxidizing said Af-unsaturated steroids with an oxidizing agent capable of oxidizing to a ketone group a methylene group adjacent to a double bond, said oxidizing agent being selected from the group consisting of compounds of hexavalent chromium, compounds of heptavalent manganese and selenium dioxide, thereby obtaining at least one member of the class consisting of A-androstenedione-3,17. and A -pregnenedione-3,20. v

13. The process which comprises subjecting a steroid of the formula,

CH3 CH7;

where R" is a sterol-side chain containing 8 to 10 carbon atoms and X is selected from the class consisting of chlorine and bromine to oxidative side chain degradation by treatment; with anoxidizing agent selected from the class consisting f chromic acid, permanganic acid, and their salts, treating the oxidation products thus obtained with a dehalogenating agent, and oxidizing the resulting M-unsaturated ketonic steroids with an oxidizing agent capable of oxidizing to a ketone group a methylene group adjacent to a double bond, said oxidizing agent being selected from the group consisting of compounds of hexavalent chromium, compounds offheptavalent manganese, and selenium dioxide, thereby obtaining at least one member of the class'consisting of M-androstenedione-SA'? and A -pregnenedime-3,20. I

14. The process which comprises subjecting a stearoid oi the formula,

16. The process which comprises oxidizing 5- chlorocholestane with an excess of chromic acid in acetic acid at 35-60 C., dehydrohalogenating the ketonic steroids thus obtained with an alkali metal salt of an organic acid, and oxidizing the resulting (i -unsaturated ketonic steroids with chromic .acid in acetic acid at 30-60 0., thereby obtaining at least one member of the class consisting of A -androstenedione-3J'7 and A-pregnenedi0ne-3,20.

1'7. A -Androstene-17-ol acylates.

18. M-Androstene-l'l-ol.

19. A process of the character described which comprises treating an androstane-l'I-one, contaming only a double bond in the rings A and B, with an agent capable of transforming the group --C0- into the group CII(OH)-, then with an esterifying ageniaand then causing the product thus obtained to react with an oxidizing agent capable of introducing a keto group into the a-position of double bonds.

20. The dimethyl cyclopentanopoly-hydrophenanthrene compounds containing in the 1'!- position an oxo-group and in the rings A and B only a carbon double bond.

21. The dlmethyl cyclopentanopolyhydrophenanthrene compounds containing in the l'l-position an oxo-group and in the rings A and- B only a carbon double bond in 4:5-position.

22. The A -androstene-1'7-one oi the formula:

23. The step which comprises treating a steroid ottheformula a on: on,

Q (\J \J dizing to a ketone group a methylene group adjacent to a double bond, said oxidizing agent being selected from the group consisting of compounds of hexavalent chromium, compounds of heptavalent manganese, and selenium dioxide, thereby obtaining at least one member of the class consisting of A -androstenedione-3,17, and A -pregnenedione-3,20. 15. The process which comprises oxidizing 5,6

dibromocholestane with an excess of chromic acid in acetic acid at 35-60 C., dehalogenating with zinc dust the oxidation'products thus obtained, converting the resulting M-unsaturated ketonic steroids to the corresponding n -unsaturated steroids by addition thereto and subsequent removal therefrom of an agent selected from the class consisting of hydrogen chloride and hydrogen bromide, and oxidizing said ,A -unsaturated steroids with chromic acid in acetic acid at 30-60 0., thereby obtaining at least one member of the class consisting of M-androstenedione- 3,37 and A*-pregnenedione-3,20.

where Q is a member of the class consisting of and i O-acyl with an oxidizing agent capable of oxidizing to a ketone group a methylene group adjacent to a double bond, said oxidizing agent being selected from the group consisting of compounds of I of the formula on, on;

' dioxide, thus forming A*-androstenedione-3,17.

where Q is a member of the class consisting of (=0), v

- on 0-adyl and 'androstenone-1'I with chromic acid in acetic acid at 30-60" 0., thus forming M-androstenedione- 3,17;

27. A compound of the forgnula CH: CH;

where Q is a member of the class consisting of (=0),

. and

RUSSELL EARL MARKER. EUGENE L. WITI'LE.