US3766248A

US3766248A - Substituted tricyclic compounds and process for their preparation

Info

Publication number: US3766248A
Application number: US00017855A
Authority: US
Inventors: L Nedelec; R Bucourt
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1966-03-22
Filing date: 1970-03-09
Publication date: 1973-10-16
Anticipated expiration: 1990-10-16
Also published as: US3574688A

Abstract

THIS INVENTION RELATES TO NOVEL SUBSTITUTED TRICYCLIC COMPOUNDS OF THE FORMULA

3-(X-O-),3A-R,7-(O=),6-(HO-CH2-)-1,2,7,8,9,9A-HEXAHYDRO-

3H-BENZ(E)INDENE

WHEREIN R IS ALKYL HAVING FROM 1 TO 6 CARBON ATOMS, X IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL HAVING FROM 1 TO 5 CARBON ATOMS, ALKENYL HAVING FROM 3 TO 5 CARBON ATOMS, ALKOXYALKYL HAVING FROM 2 TO 5 CARBON ATOMS, ARALKYL HAVING FROM 7 TO 11 CARBON ATOMS, CYCLOALKYLALKYL HAVING FROM 4 TO 11 CARBON ATOMS, ALKYLTHIOALKYL HAVING FROM 2 TO 5 CARBON ATOMS, CYCLOALKYL HAVING FROM 4 TO 7 CARBON ATOMS, AND THE ACYL OF AN ORGANIC CARBOXYLIC ACID HAVING FROM 1 TO 18 CARBON ATOMS, AS WELL AS THE PROCES OF PREPARING THE SAME. THESE COMPOUNDS ARE USEFUL AS INTERMEDIATES IN THE PREPARATION OF 2-OXA STEROIDS OF THE FORMULA

3-(O=),13-R,17-(X-O-)-2-OXAESTRA-4,9,11-TRIENE

WHICH HAVE AN ANABOLIC ACTION COUPLED WITH AN ANDROGENIC ACTION.

Description

United States Patent Ofice 3,766,248 Patented Oct. 16, 1973 Int. Cl. C07c 49/38, 69/24, 69/78 US. Cl. 260476 C 15 Claims ABSTRACT OF THE DISCLOSURE This invention relates to novel substituted tricyclic compounds of the formula R jU OX ITO-CH,

wherein R is alkyl having from 1 to 6 carbon atoms, X is selected from the group consisting of hydrogen, alkyl having from 1 to carbon atoms, alkenyl having from 3 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 4 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, cycloalkyl having from 4 to 7 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, as well as the process of preparing the same. These compounds are useful as intermediates in the preparation of 2-oxa steroids of the formula which have an anabolic action coupled with an androgenie action.

REFERENCE TO PRIOR APPLICATIONS This application is a continuation-in-part of our copending applications Ser. No. 603,094, filed Dec. 20, 1966, now US. Pat. No. 3,574,688, and Ser. No. 728,880, filed May 14, 1968, this latter application being a continuation-in-part of Ser. No. 603,457, filed Dec. 21, 1966, and now abandoned.

OBJECTS OF THE INVENTION An object of the present invention is the obtention of a substituted des-A steroid of the formula wherein R is an alkyl having from 1 to 6 carbon atoms, X is a member selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 4 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, cycloalkyl having from 4 to 7 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms.

Another object of the present invention is the development of a process for the production of the above substituted des-A steroids which comprises the steps of formylating the des-A-A -gonene of the formula wherein R is an alkyl having from 1 to 6 carbon atoms, X is a member selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 4 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, cycloalkyl having from 4 to 7 carbon atoms, and the acyl of an organic carbocyclic acid having from 1 to 18 carbon atoms, by the action of a formylating agent, dehydro genating the resulting IO-hydroxymethylene enone of the formula HO-CH wherein R and X have the above-assigned meanings, by the action of a dehydrogenating agent, reducing the resulting formyl dienone of the formula all A yet further object of the invention is the development of a process for the production of a 10-hydroxymethyleneefione 'of'the'formula i wherein R is an alkyl having from 1 to 6 carbon atoms, X is a member selected from the group consisting of hydrogen, alkyl having from 1 to carbon atoms, alkenyl having from 3 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 4 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, cycloalkyl having from 4 to 7 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, which comprises the steps of condensing an enamine of the formula wherein R, R R and X have the above-assigned meanings, by the action of an acid, and recovering said 10- hydroxy-methylene enone.

A still further object of the invention is the obtention of .an intermediate steroid precursor selected from the group consisting of (1) a IO-hydroxymethylene enone of the formula R I OX I-IO-CII and (2) a 10-formyl-dienone of the formula wherein R is an alkyl having from 1 to 6 carbon atoms, X is a member selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 4 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, cycloalkyl having from 4 to 7 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms and A is a member selected from the group consisting of oxygen and a ketal group.

These and other objects of the present invention will become more apparent as the description of the invention proceeds.

DESCRIPTION OF THE INVENTION The invention relates to new cyclopentanopolyhydronaphthalene derivatives, which for a better understanding will be designated in the following by the terms usually used in steroid chemistry, that is to say, their names are derived from those of the corresponding tetracyclic compounds by having them preceded with the prefix des-A.

These new Des-A steroid derivatives of the invention are represented by the general Formula I wherein R is an alkyl having from 1 to 6 carbon atoms, and X is selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 4 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, cycloalkyl having from 4 to 7 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms.

In the general Formula I the alkyl, R, is advantageously one of the following: methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

The new compounds of the general Formula I are useful as intermediates in the synthesis of the 2-0Xa steroids of the general formula wherein R and X retain the previous significance. These 2-oxa steroids possess particularly an important anabolic action and an androgenic action.

The process for the preparation of these 2-oxa steroids consists in that a compound of the general Formula I is condensed with an alkyl haloacetate, preferably a lower alkyl haloacetate such as ethyl bromoacetate, in the presence of zinc, preferably at the reflux temperature of the solvent employed, and in that the condensation product is treated with an acid agent, preferably a strong mineral or organic acid such as hydrochloric acid or p-toluene sulfonic acid.

The reaction formula given below illustrates the process for the preparation of the said 2-oxa steroids.

R m HO-CH; l "i R and X have the above-assigned meanings.

The process for the preparation of the compounds of the general Formula I, a further object of the invention, is characterized in that by the reaction of a formylation agent with a des-A-A -gonene-5-one of the general Formula II R and X retaining, here and in the following, the aboveassigned meanings, the corresponding IO-hydroxymethylene enone of the general Foormula III (III) is obtained which under the action of dehydrogenation agent leads to the formyl dienone of the general Formula IV 0 l Hitthe aldehyde group of which is selectively reduced into an alcohol group with the aid of a mixed alkali metal 6 hydride selected from the group consisting of an alkali metal borohydride and tri-t.-butoxy-aluminum-lithium hydride, and the desired hydroxymethyl dienone of the general Formula I HO-CHris obtained.

The formylation is preferably realized according to the method of Vilsmeyer Haack (Ber. 60B, 119 [1927]). For example, the dimethylformamide-phosphorus oxychloride complex is used, but it is evident that other complexes of other substituted formamides, for example, N,N-disubstituted formamides such as N-methyl-N-phenylformamide or N-piperidino-N-methylformamide, with other inorganic chlorination agents, for example, phosgene, sulfuryl chlo ride or phosphorus pentachloride are also suitable.

The reaction is effected in an organic solvent, for example, methylene chloride, working at room temperature or in the neighborhood of room temperature.

The dehydrogenation of the 10 hydroxymethylene enone of the general Formula III is effected with the aid of a substituted p-quinone, preferably a halo or cyano substituted p-benzoquinone selected from the group consisting of halo-substituted p-benzoquinones, cyano-substituted p-benzoquinones and halo-cya-no-substituted p-benzoquinones, such as 2,3-dichloro 5,6 dicyano-p-benzoquinone, 2,3-dibromo-5,6-dicyano-p-benzoquinone, 2,3,5, 6-tetrachloro-p-benzoquinone, 2,3-dicyano 5 chloro-pbenzoquinone and 2,3-dicyano-p-benzoquinone. Advantageously, the work is carried out in dioxane.

The alkali metal borohydride utilized for the selective reduction of the aldehyde function of the dienic compound of the general Formula IV is preferably sodium or potassium borohydride. The reaction is conducted in a solvent such as aqueous dioxane, while slightly cooling and utilizing the theoretical amount of borohydride.

A variant of the process of the invention consists in that instead of the starting tricyclic ketone of the general Formula II, the corresponding enamine of the general FormulaA R I OX Rr-IIT I HO-CH Ra Ra is subjected to an acid hydrolysis to obtain the corresponding lO-hydroxymethylene enone of the general Formula III (III) The synthesis is then proceeded with as described above.

Preferably, in the general Formulal, R can be methyl, ethyl and propyl; and X can be hydrogen, alkyl having from 1 to 5 carbon atoms such as methyl, ethyl, propyl, 7

alkanoic acids, such as acetic acid, propionic acid, lauric acid, etc.,alkenoic acids such as oleic acid, etc., benzoic acid, hexahydrobenzoic acid, cycloalkylalkanoic acids, such as cyclopentyl-, cyclohexyl-, acetic or propionic acids, etc., phenylalkanoic acids such as phenylacetic acid,

phenylpropionic' acid etc., phenoxyalkanoic acids such as phenoxyacetic acid, heterocyclic carboxylic acids suchas furan-Z-carboxylic acid, S-terbutylfuran 2 carboxylic acids, etc., and fl-keto-alkanoic acids such as acetylacetic acid, etc. 7 a

It is preferred to utilize the benzoate ester in the synthesis of the invention. However, the 17-ethers and the 17-alcohol can also be utilized. Among thel'7-ethers are the 17,8-methoxy, the 17B-ethoxy, the 17/3-allyloxy, the l7fi-methoxymethoxy, etc.

The starting products of the present process can be obtained, for example, according to the processes described in French Pat. No. 1,234,734, in Belgian Pat. No. 599,342 and in US. Pat. No. 3,168,530. 7

Another variant of the process of the invention consists in that instead of the starting tricyclic ketone ofthe general Formula II, the corresponding tricyclic ketone where X is the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms or the corresponding enamine is utilized as the starting compound. This variant, following the above procedures results in the formyl dienone of the general Formula'IV where X is acyl. The 1O-formyl-des-A-A -gonadiene-5-one thus formed, of the Formula IV (X=acy1) wherein R has the above-assigned meanings and acyl repfrom 1 to 18 carbon atoms, is reacted with a ketalizing agent. The resultant diketal of. the Formula VII --O Acyl v11) wherein K is a ketal group, R and Acyl have the aboveassigned means, is saponified by the action of an alkaline agent. The resultant 17,13-01 derivatives of the Formula VIII the (VIII) wherein K and. R have the above-assigned"meanings, is etherified by the action of a halogenide of the formula wherein Hal is a halogen atom other than fluorine, and

to 18 carbon atoms selected from the group consisting of t X is selected from the group consisting of alkyl'having from 1 :to 5 carbon atoms, alkenyl' having from 3 to 5 carbon atoms, ,cycloalkyl having from 4 to 7 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkyla alkyl having from 4 toll carbon atoms, and alkylthioalkyl having from 2 to 5 carbon atoms. The resultant 1'7- ether of the Formula IX resents the acyl of an organic carboxylic acid having wherein R, K and X have the above-assigned meanings, is subjected to an acid hydrolysis, such as an aqueous organic acid. The resultant 10-formyl-des-A-gonadiene of the Formula IV (where X=X) t/\ o= w O wherein R and X have the above-assigned meanings, is reduced by the action of a mixed alkali metal hyrride, and the lO-hydroxymet-hyl derivative of Formula I, where X=X, is recovered.

The execution of the above variant of the process of the invention can preferably be effected in the following manner: a

(a) The ketalizing agent is selected from the group consisting of the lower cyclic ketals, preferably the 2-dilower alkyl-dioxolanes, for example, Z-methyl- -et-hyl-di oxolane, and the lower alkanediols, for example, ethyleneglycol. The reaction is conducted in the presence of an acid catalyst, preferably a strong organic catalyst, such as p-tolueneslalfonic acid.

(b) The alkaline agent used in the saponification step is an alkali metal hydroxide, such as sodium or potassium hydroxide, in the presence of a lower alkanol such as methanol or ethanol.

(c) The etherification step is carried out in the presence of a basic agent, for example, a metal hydride such as sodium hydride, in a polar solvent such as tetrahydrofuran, dimethylformamide or dimethylsulfoxide.

(d) The mixed hydride is selected from the group consisting of an alkali metal borohydride, such as sodium borohydride, and an alkali metal hydridotrialkoxoaluminate, such as lithium hydridotriisobutoxoaluminate. The reaction is preferably performed in aqueous dioxane in the first case, and in tetrahydrofuran in the second case.

The following examples will serve for better comprehension of the invention. However, it is to be understood that they do not limit the invention in any manner.

EXAMPLE I Preparation of lo-hydroxymethyl-13fl-methyl-l7B-benzoyloxy-des-A-A": -gonadiene one (or -hydroxymethyl- 17fi-benzoyloxy-des-A-A -estradiene-5-one) Step A: Preparation of 10 hydroxymethylene-Bfimethyl-17B-benzoyloxy-des-A-A -gonene 5 one (or 10-hydroxymethylene 17B benzoyloxy-des-A-A -estene-5-one).- Dropwise and while agitating at room temperature, 15 cc. of anhydrous phosphorus oxychloride were introduced into 6.2 cc. of anhydrous dimethylformamide, and the solution was allowed to stand for 2 hours.

At the same time, 3 gm. of 13B-methyl-17B-benzoyloxy-des-A-A -gonene-5-one (described in French Pat. No. 1,234,734) were placed in suspension in 3 cc. of methylene chloride.

The temperature of the suspension was lowered to 16 C. Then 6 cc. of the phosphorus oxychloride-dimethylformamide complex, prepared as previously described, were introduced therein under vigorous agitation, without exceeding a temperature of 20 C., and the reaction mixture was agitated for 10 minutes more.

Thereafter, the reaction mixture was poured into iced water, agitated for several minutes, extracted first with benzene, then with ether. The resultant extracts were combined, washed with water and decanted. 2 cc. of formic acid were added to the washed extract and the agitation was continued under an atmosphere of nitrogen for about 1 /2 hours. Thereafter, the solution obtained was washed first with an aqueous tartaric acid solution, then with water, with a 5% potassium carbonate solution in water and lastly with water.

Next, the desired product was isolated by washing the organic extract with an iced aqueous solution of 0.28 N potassium hydroxide. After acidification of the aqueous solution of the potassium salt with sulfuric acid to a pH of 3 to 4, the solution was extracted with ether, which was dried and the solvent was evaporated. A residue was obtained which crystallized on addition of ethanol.

After recrystallization from isopropanol containing 10% of water, pure 10 hydroxymethylene-13fi-methyll7fi-benzoyloxy-des-a-A -gonene-5-one, having a melting point of 129 to 130 C., was obtained with a yield of 34%.

The product was insoluble in water and in dilute aqueous acids, slightly soluble in cold alcohols and isopropylic ether, and soluble in dilute aqueous alkalis, hot alcohols, ether, chloroform, methylene chloride, toluene and ethyl acetate. It gave an intense blue reaction with ferric chloride.

Analysis.Calculated for C H O (molecular weight =352.41) (percent): C, 74.97; H, 6.86; O, 18.16. Found (percent): C, 75.0; H, 7.0; O, 18.1.

This compound is not described in the literature.

Step B: Preparation of 10-formyl-l3 8-methyl-17/3-benzoyloxy-des-A-A -gonadiene-5-one.-At room temperature, 10.6 gm. of IO-hydroxymethylene-l3B-methyl-17/8- benzoyloxy-des-A-A -gonene-5-one were dissolved in 106 cc. of anhydrous dioxane. The solution was slightly cooled, and, in the space of a few minutes, 7.15 gm. of

2,3 dichloro 4,6-dicyano-p-benzoquinone were added thereto. The reaction mixture was agitated for 1 hour under an atmosphere of nitrogen.

Next, the reaction mixture was filtered and the insoluble portion was washed with methylene chloride. The filtrate was poured into water and extracted with ether.

The extracts obtained were washed successively first with a saturated aqueous solution of sodium bicarbonate, then with a N sodium hydroxide solution, with water and finally salt water. The extract was then dried, distilled under vacuum, and the residue was crystallized by trituration in ether.

The crystals were vacuum filtered, and 4.14 gm. of 10- formyl 13B methyl-17,8-benzoyloxy-des-A-A -gonadiene-S-one, that is 39% of the theory, were obtained. The product after recrystallization from ethanol had a melting point of 137 to 138 C., and a specific rotation [a] =62.3 (c.=0.94% in chloroform).

Infrared spectra (chloroform):

CHO at 1690 cmand CH at 2750 cm." C=O at 1665 cm.- C=C at 1593 cm. and 1543 cm. Benzoate at 1715 cm.- and 1279 cmr Ultraviolet spectra:

( 1) Dioxanea at 230 ma, 1:": 19,000 and 303-304 III/1., e=21,000 (2) Ethanol and N/10 sodium hydroxide- Amax' at 231 Ill/L, e=21,000 and 259 mu, 6: 14,000 and 333 m e=7,900.

A naIysz's.Calculated for C H O (molecular weight =350.40) (percent): C, 75.40; H, 6.33. Found (percent): C, 75.7; H, 6.5.

The product was slightly souble in alcohol and ether, and soluble in chloroform.

This compound is not described in the literature.

Step C: Preparation of 10-hydroxymethyl-l3fi-methyl- 17 3 benzoyloxy-des-A-A -gonadiene-S-one (or 10-hydroxymethyl 17B benzoyloxy-des-A-A -estradiene-5- one).At room temperature, 4.63 gm. of 10-formyl-13B- methyl-17fi-benzoyloxy-des-A-A -gonadiene-5-one were dissolved in a mixture of 46 cc. of anhydrous dioxane and 4.6 cc. of water. The mixture was cooled to about 5 C.; then slowly, while agitating under an atmosphere of nitrogen, 0.141 gm. of sodium borohydride were introduced therein. The agitation was maintained for V2 hour. Then the reaction mixture was poured into water and extracted with methylene chloride.

The extracts obtained were washed first with water, then with salt water, dried and distilled to dryness under vacuum. The residue was dissolved in the minimum of a mixture of benzene and ethyl acetate (2:3) and subjected to chromatography through silica gel with the same mixture of solvents.

In this way, a crystallized product was obtained which, after recrystallization from ethyl acetate admixed with ether, furnished 2.6 gm. of 10-hydroxymethyl-13,8-methyl- 17,8 benzoyloxy des A-A -gonadiene-5-one, that is a yield of 56%, with a melting point of 134 to C. and a specific rotation [u] =-69.2 (c.-=0.9% in chloroform).

The product was insoluble in water, slightly soluble in ether, and soluble in alcohol and chloroform.

Infrared spectra (chloroform):

C=O and C=C at 1645 cm.- and 1605 cm. Associated OH between 3560 and 3400 cm.- Ultraviolet spectra (in ethanol):

A 230 III/.0, 15,050 a 285 m e=25,500

Analysis.Calculated for C H O (molecular weight =352.41) (percent): C, 74.97; H, 6.86. Found (percent): C, 74.8; H, 6.8.

This compound is not described in the literature.

The dehydrogenation step of Example I may be efiected also in the following way:

Step B: Preparation of 10 formyl 13d methyl-17,8- benzoyloxy-des-A-A -gonadiene--one.At room temperature, under stirring, 1 gm. of -hydroxymethylene- 13B methyl 17B-benzoyloxy-des-A-A -gonene-S-one, obtained in the step A of Example I, was poured, in a suspension made of Tetrachloro-2,3,5,6-benzoquinone, gm. 1 Dioxane, cc. 8

The reaction mixture was kept under stirring for two 7 The. crystalline residue was dried under vacuum. The V 10 -.formyl 13B methyl-175-benzoyloxy-desA-A gonadiene-S-one was obtained with a yield of 0.895 gm.

(90% of the theory). e

This compound was purified by triturating' with ethylether. The pure sample for analysis melted at 135 then 138".

It did not depress the melting point'of the compound obtained at the step B of this example.

EXAMPLE 11' Preparation of 10 hydroxymethylene 13 B methyl-17B- benzoyloxy des-A-A -gonene-5-one (or IO-hydroxymethylene 17/3 benzoyloxy des-A-A -estrene-5- one) starting with the enamine of 13,8-methyl-17B- benzoyloxy-des-A-A -gonene-5-one 1 gm. of 5-pyrrolidyl-13,8-methyl-l7,B-benzoyloxy-des- A-A -gonadiene, described in 'French Pat. No. 1,271,997 was dissolved in 5 cc. of anhydrous dioxane. The solution was cooled to a temperature of 10 C. 0.37 cc. of triethylamine were added and then 09 cc. of mixed formic acetic anhydride (J.A.C.S., 61, 33551 [1939]) were introduced dropwise therein.

Next, the reaction mixture was agitated for /2 hour at a temperature of about 10 C. and under an atmosphere of nitrogen. Then 2 cc. of water were added and the agitation was maintained for 2 hours altogether. Thereafter, it was poured into water and extracted. with ether. The extracts were washed first with water, then with a saturated aqueous solution of sodium bicarbonate and lastly with an iced solution of N/ 10 sodium hydroxide.

The washed extract was acidified with hydrochloric acid and extracted with ether. The extracts were washed as described in the preceding but with a final washing with 12 nitrogen, 27.23 gm. of 5-pyrrolidino-13B-ethyl-17B- benZOyl0xy-desA-A -gonadiene (obtained according to the process described in US. Pat. No. 3,168,530) were dissolved in 272 cc. of dioxane and 136 cc. of tetrahydrofuran. Then, 20 cc. of triethylamine and, while maintaining the temperature between 0 C. and +5 C., 50 cc. of formic-acetic acid anhydride (obtained by the action of sodium formate on the acetyl chloride) were added thereto. Next, the mixture was agitated for 3 hours and minutes. Then, 110cc. of water were added and the reaction mixturewas allowed to stand overnight at room temperature. Thereafter the reaction mixture was poured ino a water-ice mixture. The precipitate was extraeted with ether. The ethereal phase were separated and washed with water, then extracted with N/ 2 sodium hydroxide-ice mixture. The alkaline phase were acidified with hydrochloric acid to a pH of 1, and extracted with ether. The ethereal phases were washed with water, dried and distilled to dryness. The residue obtained was purified by dissolution in hot'ethanol, which was then allowed to return to room temperature. Next, the mixture was iced for 30 minutes and vacuum filtered. The precipitate was washed first with ethanohthen with petroleum ether and finally dried. I 14.72 gm.- of lO-hydroxymethylenel3flethyl-17/3-benzoyloxy-des-A-A -gonene-5-one were obtained in. the form of'clear, yellow crystalssoluble in water, dried, filtered and evaporated to dryness. The residue was recrystallized from ethanol, thus obtaining 0.17

gm. of ,IO-hydroxymethylene-l3fl-methyl-17p-benzoyloxy- EXAMPLE III Preparation, of IO-hydroxymethyl-l3fi-ethyl-Uri-benibyl;

oxy-des-A-A -gonadiene-S-one Step A: Preparation of 10-hydroxymethylene-l3fiethyl 17fi-benzoyloxy-des-A-A -gonene-5-one.-At room temperature, under agitation and an atmosphere of acetone, chloroform and methanol, and insoluble in water. The product had a melting point of 118 C. and a specific rotation [oc] =+58;L-2' (c.=0.5% in chloroform) Analysis.CalCulated for C H O (molecular weight=366.44) (percent): C, 75.38 H, 7.15. Found (percent): C, 75.1; H, 6.9.

This compound is not described in the literature.

Step B: Preparation of 10-formyl-13B-ethyl-17B- benzoyloxy-desA-a -gonadiene-5-one.At room temperature, under agitation and an atmosphere of nitrogen, 14.72 gm. of 10 hydroxymethylene 13B ethyl- 17 3- benzoyloxy-des-A-A -gonene-S-one were dissolved in a mixture of cc. of dioxane and 75 cc. of etherrA. solution of 10.5 gm. of dicyanodichlorobenzoquinone in 75 cc. of dioxane was added while maintaining the interior temperature between 8. C. and 10 C. Then, the mixture was agitated over a period of 45 minutes at room temperature. Next, the reaction mixture was poured into an iced solution of sodium bicarbonate and sodium bisulfite' and extracted with ether. The ethereal phases were washed first with a mixture of 0.1 N sodium hydroxide and ice, then with water and finally distilled to dryness. 7.47 gm. of rawproduct werethus recovered, which was purified by chromatography through a column of alumina and eluation with methylene chloride. In this manner, after evaporation of the solvent, 5.33 gm. of 10 formyl- 13,8 ethyl 17 3-ben2oy1oxy-des-A-A -gonadiene-S-one were obtained, which product was used as such in the next a des-A-A -gonadiene-5-one were dissolved in 54 cc. of

of dioxane. The temperature was brought to +5 C., and

180 mg. of sodium borohydride were added to the solu tion. The reaction mixture was kept:under agitation for one .hour, then poured into a water-ice mixture. The mix? ture was then extracted with methylene chloride. Next,

the methylene chloride phases were washed with water, dried and distilled to dryness. The resultant residuewas subjected to chromatography through alumina and eluted with methylene chlorideeAfter the evaporation of the solvent, 3.15 gm. of IO-hydroxymethyl-l3B-ethyl-17/3- benzoyloxy-des-A -gonadiene-5-one were obtained.

For analysis, theproduct was recrystallized from ether and petroleum ether. This compound occurred in the form of yellowish crystals, soluble in acetone, chloroform and alcohol, and insoluble in water. It had a melting point of 90 C. and a specific rotation [rx] =74i2 (c.=0.2% in chloroform).

Analysis.-Calculated for C H O (molecular weight:366.44) (percent): C, 75.38; H, 7.15. Found (percent): C, 75.2; H, 7.3.

This compound is not described in the literature.

EXAMPLE IV of l-hydroxymethyl-13fl-methyl-17,8-benzyloxy-des-A-A -gonadiene--one Step A: Preparation of 5-ethylenedioxy-10-(ethylenedioxy)-methyl-13/3-methyl-17B-benzoyloxy-des-A -gonadiene-5 gm. of 10-formyl-13(3-methyl-17/3-benzoyloxydes-A-A -gonadiene-S-one (as described in Example I, step B) and 0.15 gm. of paratoluene sulfonic acid were introduced into 150 cc. of chloroform and cc. of ethylene glycol under an atomsphere of nitrogen. The mixture was heated to reflux under agitation for hours. The distillate was dried over a dehydrating agent before being recycled. Then 0.05 gm. of paratoluene sulfonic acid was added and the mixture was again heated to reflux under the previously described conditions for 15 hours. The reaction mixture was cooled, made alkaline by addition of triethylamine and diluted with water. The aqueous phase was extracted with methylene chloride, and the extracts were combined with the organic phase. The organic solution thus obtained was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with an ethyl acetate-benzene mixture (1:9). 2.4 gm. of raw mono-ketal (M.P. 192 C.) were first eluted; then 1.7 gm. of raw diketal (M.P. 175 C.) was collected.

After recrystallization of the raw diketal from ethanol, 1.27 gm. of pure 5 ethylenedioxy-10-(ethylenedioxy) methyl-13p-methyl-17,8-benzoyloxy-des-A-A -gonadiene, having a melting point of 176 C., was obtained.

Analysis. Calculated for C H O (molecular weight=438.5) (percent): C, 71.2; H, 6.9. Found (percent): C, 71.2; H, 7.2.

Ultraviolet spectrum (in ethanol): kmax, at 239-240 ma, e=32,850.

Step B: Preparation of 5 ethylenedioxy-10-(ethylenedioxy) methyl des A A gonadiene 17,8 ol. A mixture of 4.77 gm. of 5 ethylenedioxy-10-(ethylenedioxy) methyl 13/3-methyl-17,8-benzoyloxy-des-A-A gonadiene and 48 cc. of a N potassium hydroxide solution in 95% ethanol was heated to reflux for 30 minutes and then 250 cc. of water were added. The reaction mixture was extracted with methylene chloride. The organic phases were washed with water, dried over sodium sulfate, filtered and evaporated to dryness under vacuum to yield 3.8 gm. of raw l7fi-hydroxy derivative. 200 mg. of raw product were pasted in isopropyl ether at reflux temperature. After cooling, the precipitate was filtered, washed with isopropyl ether and dried, whereby 175 mg. (92% yield) of product were obtained. This product was purified by recrystallization from ethyl acetate, thus affording 105 mg. of 5 ethylenedioxy-lO-(ethylenedioxy) methyl-13B- methyl-des-A-A -gonadiene-175-o1. The product occurred in the form of colorless crystals, soluble in ethanol and methylene chloride, insoluble in water, and melting at 183 C.

Analysis. Calculated for C H O (molecular weight=33440 (percent): C, 68.24; H, 7.84. Found (percent): C, 68.4; H, 7.5.

Ultraviolet spectrum (in ethanol): Amax. at 247 m e=23,200.

Step C: Preparation of 5-ethylenedioxy-10-(ethylenedioxy) methyl 13/3 methyl-l7,8-benzyloxy-des-A-A gonadiene.-8.5 gm. of 5 ethylenedioxy-l0-(ethylenedioxy) methyl 13,8-methyl-17/3-hydroxy-des-A-A -gonadiene were dissolved in 180 cc. of tetrahydrofuran. Then 3.2 gm. of a suspension of 50% sodium hydride in par- Preparation affin oil were added to the solution, and the whole was heated to reflux for 30 minutes. Then 12.5 cc. of benzyl bromide were added, and the heating at reflux was continued for a period of minutes. The reaction mixture was cooled to room temperature and poured into a mixture of water, ice and aqueous sodium hydroxide solution. The aqueous phase was extracted with methylene chloride, the extracts were combined, washed with water, dried and concentrated to dryness. The residue was triturated with petroleum ether (B.P. 65-75 C.) to afford 7.65 gm. of 5 ethylenedioxy-10-(ethylenedioxy) methylmethyl-17B-benzyloxy-des-A-A -gonadiene melting at C.

The analytical sample, MP. 163 C., was obtained by recrystallization from methanol containing 2 parts per thousand of triethylamine.

Analysis. Calculated for C H O (molecular weight:424.52) (percent): C, 73.57; H, 7.59. Found percent: C, 73.5; H, 7.8.

Ultraviolet spectrum (in ethanol): m at 246 mp, e=23,600.

Step D.: Preparation of 10-formyl-l3B-methyl-l7B- benzyloxy-des-A-A -gonadiene 5 one.-Under an atmospheric of nitrogen, 7.98 gm. of 5-ethylenedioxy-10- (ethylenedioxy) methyl-13/3-methyl-l7fi-benZyloxy-des-A- A- -gonadiene were dissolved in 60 cc. of acetic acid, then 20 cc. of water were added and the mixture was stirred at room temperature for 1 hour. Then a water-ice mixture was added, and the precipitate thus formed was vacuum-filtered, washed with water and dried to yield 6.05 gm. of raw '10-formyl-13/3-methyl-l7[3-benzyloxydes-A-A -gonadiened-one, having a melting point of 120 C., which product was used as such in the next step.

Stept. E: 10-hydrox'ymethyl-l3B-methyl-17/3-benzyloxydes-A-A -gonadiene-5-one.Under an atmosphere of nirtogen, 6.84 gm. of raw 10-formayl-13/8-methyl-l7fibenZyloxy-des-A-A -gonadiesne-S-one were dissolved in 70 cc. of dioxane. The mixture was cooled to +10 C., and a cold solution of 0.200 gm. of sodium borohydride in 7 cc. of water was added dropwise. The re action mixture was stirred for 20 minutes, and 0.020 gm. of sodium borohydride was then added. After an additional stirring at +10 C. for 10 minutes, the mixture was poured into water. The aqueous layer was extracted with methylene chloride, the combined extracts were washed, first with Water, then with a N/ 10 sodium hydroxide aqueous solution and finally with Water. The extracts were dried and concentrated to dryness. The residue was purified by chromatoography through silica gel to aflord 4.14 gm. of 10-hydroxymethyl 13/3 methyl 17B benZ'yloxy-des-A- A -gonadiene-5-one, having a melting point of 115 C.

EXAMPLE V Preparation of 10-hydroxymethyl-13/3-methyl-17B-hexahydrobenzyloxy-des-A-A -gonadiene-S-one Step A: 5 ethylenedioxy 10-(ethylenedioxy)-methyl- 13/3 methyl 17B hexahydrobenzyloxy des-A-A gonadiene.-By following the procedure of step C of Example IV, S-ethylenedioxy-l0-(ethylenedioxy)-methyl- 13fl-methyl-deS-A-A -gonadiene-17l3-ol was reacted in a dimethyl sulfoxide tetrahydrofuran mixture with hexahydrobenzyl bromide to give S-ethylenedioxy-IO-(ethylenedioxy) methyl-13,8-methyl-17fi-hexahydrobenzyloxy-des- A-A -gonadiene, having a melting point of C. and a specific rotation [a] =12Z (c.=0.5% in chloroform).

Ultraviolet spectrum (in ethanol): A at 247 mu, e=23,700.

This compound is not described in the literature.

Step B: 10- formyl 13/3-methyl-17,8-hexahydrobenzyloxy des A-A -gonadiene-5-one.-Following the procedure of step D of Example IV, S-ethylenedioxy-10-(ethylenedioxy) methyl l3B-methyl-17fi-hexahydrobenzyloxydes-A-n -gonadiene was converted by acetic acid hydrolysis, into 10-formyl-13,8-methyl-17,8-hexahydrobenzyloxy-des-A-A -gonadiene-S-one, having a melting'point of 107 C. and a specific rotation [a] =115 (c.=0.6% in chloroform). This material was used as such in the next step.

Step C: l-hydroxymethyl-13fl-methyl-17/3-hexahydrobenzyloxy-des-A-A -gonadiene--one.-By following the procedure of step E of Example IV, the material obtained under step B above was converted by treatment with sodium borohydride into raw -hydroxymethyl-13B- methyl 17B hexahydrobenzyloxy-des-A-A -gonadiene- 5-one.

EXAMPLE VI Preparation of 10-hydroxymethyl- 13B-methyl- 1715'- (2.- methyl) -allyloxy-des-A-A -gonadiene-5 -one Step A: 5 ethylenedioxy 10-(ethylenedioxy)-methyl- 13B methyl 17/3 benzoyloxy-des-A-A gonadiene.- This compound was obtained as described in Example IV, step A.

Step B: Preparation of 5 ethylenedioxy-10-(ethylenedioxy) methyl 13;3 methyl-des-AA -gonadine-17 3- ol.This compound was obtained as described in' Ex ample IV, step B. a

Step C: 5 ethylenedioxy-lO-(ethylenedioxy) methyl- 135 methyl-17/3-(2'-methyl) allyloxy-des-A-A -gonadiene.2.4 gm. of a suspension of 50% sodium hydride in mineral oil and 24 cc. of tetrahydrofuran were stirred at room temperature under nitrogen for a period of 5 minutes. A solution of 4.09 .gm. of S-ethylenedioxy-IO (ethylenedioxy) methyl 13B methyl-des-A-A -gonadiene-17/3-ol in 50 cc. of tetahydrofuran was added thereto and the whole was heated to reflux for 30 minutes.

A solution of 9 gm. of ,B-methylallyl chloridein 36 cc. of tetrahydrofuran was then added and the whole was added to reflux for 18 hours. After cooling, 300 ccof water were added, and the reaction mixture was extracted with methylene chloride. The extracts Were washed with water, dried over sodium sulfate, filtered, and evaporated to dryness under vacuum, thus yielding 5.55 gm. of raw 17B-methylallyl derivative which was recrystallized from isopropyl ether (yield 2.44 gm.).

Another crystallization from isopropyl ether afforded an analytical sample which occurred in the form of colorless needles, soluble in ethanol and methylene chloride and insoluble in water. It melted at 137 C. and had a specific rotation [a] =160: (c.=0.2% in chloroform).

Analysis.Calculated for C H O (molecular weight =388.49) (percent): C, 71.10; H, 8.30. Found (percent): C, 71.1; H, 8.3.

Ultraviolet spectrum (in ethanol): A at 246 to 247 m/L, e=23,100.

This compound is not described in the literature.

Step. D. Preparation of 10-formyl-13,8-methyl-l7fl-(2'- methyl) allyloxy-des-A-A -gonadiene-5-one.A solution of 2.2 gm. of S-ethylenedioxy lo-(ethylenedioxy) methyl-13B-rnethyl-l7fi-(2'-methyl) allyloxy-des-A-A gonadiene in 16.5 cc. of acetic acid and-5.5 cc. of Water was stirred under nitrogen for 1 hour at room temperature and then poured into 400 cc. of saturated aqueous solution of sodium bicarbonate. The mixture was extracted with methylene chloride, and the extracts were washed with water until the wash waters were neutral, dried over sodium sulfate, filtered and evaporated to dryness. There was obtained 1.73 gm. of 10-formyl-l3t3- methyl-l'lfl-(T-methyl) allyloxy-des-A-A -gonadiene-S- one which occurred in the form of yellow prisms, soluble in acetic acid and methylene chloride, insoluble in water. The material melted at about 58 C.

Ultraviolet spectrum (in ethanol): A at 233 mp, 'e:6,450;)\ at mu, e=19,500.

This compound is not described in the literature.

Step E: Preparation of 10-hydroxymethyl-1Fifi-methyl- 17 8-(2'-methyl) allyloxy-des-A-A g0nadiene15-one.

y-des-A-A -gonadiene-S-one were introduced into 30 cc. of dioxane and 3 cc. of water. After cooling to +8 C., mg. of sodium borohydride were added, the mixture was stirred at +10 C. for a period of 30 minutes, poured into a saturated aqueous solution of sodium chlo-' ride and extracted with methylene chloride. The organic phases'were washed with water, dried over sodium sulfate, filtered and evaporated to dryness, thus yielding 2.8 gm. of raw IO-hydroxymethyl derivative which was purifled by chromatography through silica gel followed by elution'with an ethyl acetate-benzene mixture (5-5). In this way, 1.28 gm. of IO-hydroxymethyl-l3B-methyl-17B- (2-methyl) allyloxy-des-A-A -gonadiene-5-one was obtained in the form of colorless crystals, soluble in methylene chloride, benzene and ethyl acetate, insoluble in water, and melting at 102 C.

Ultraviolet spectrum (in ethanol): k at 288' to 289 my, e=23,150. V I

This compound is not described in the literature.

EXAMPLE VII 7 Preparation of IO-hydroxymethyl-13/8-methyl-17;3-(3'- methyI-T-butenyloxy-des-A-A gonadiene-S-one Step A: Preparation of S-ethyl'enedioxy-IU-(ethylenedioxy) methyl- 13 B-methyl- 1 7,6- 3 -meLhy1-2'-butenyloxy des-A-A -gonadiene.3.4 g. of raw 5-ethylenedioxy-10- (ethylendioxy) methyl-13fi-methyl-des-A-A -gonadiene- 17/3-01 (obtained in step B of Example IV were introduced into 35 cc. of tetrahydrofuran under an atmosphere of nitrogen'and then 1 gm. of a suspension of 50% sodium hydride in paraflin oil was added. The mixture was heated to reflux for 30 minutes. Then 6 gm. of l-bromo- 3-methyl-2-butene. were introduced therein and the heating at reflux was continued for 2 hours. The reaction mixture was then cooled and subjected to hydrolysis by adding an aqueous solution of sodium bicarbonate. The aqueous layer was extracted with methylene chloride. The combined extracts were Washed with water, dried and concentrated to dryness. The residue was taken up with diethyl ether containing 0.5% of triethylamine. The precipitate was vacuum-filtered, and dried, thus affording 3.61 gm. of raw material which was recrystallized from methanol containing 1 part per thousand of triethylamine. Thus, 1.33 gm. of 5 ethylenedioxy-IO-(ethylenedioxy) methyl-13B-methyl-17B-(3'-methyl 2' butenyloxy)-des- A-A -gonadiene was obtained, which had a melting point of 144 C. and a specific rotation [a] Q=-134 (c.=0.5% in chloroform).

Analysis. Calculated for C I-1 0 (molecular weight-402.51) (percent): C, 71.61; H, 8.51. Found (percent): C, 71.8; H, 8.5.

Ultraviolet spectrum (in ethanol): A at 246 mp, e=23,500.

This compound is not described. in the. literature.

Step B: Preparation of 10-formyl-13fl-methyl-17 8-(3- methyl-2'-butenyloxy)-des-A-A -gonadiene 5 one. Under an atmosphere of nitrogen, 3.4 gm. of raw S-ethylenedioxy-IO-(ethylenedioxy) methyl -13B methyl-17 (3-methy1 2' butenyloxy)-res-A-A -gonadiene were stirred until dissolved, in 26.4 cc. of acetic acid. Next, 8 cc. of water were added and stirring was continued for 1 hour at room temperature. The reaction mixture waspoured into 400 cc. of a saturated aqueous solution of sodium bicarbonate, and the aqueous phase was extracted with methylene chloride. The extracts were washed with water, dried and evaporated to dryness, thus yielding 2.9 gm. of 10 formyl-l3fi-methyl-17fl (3'methyl-2'-butenyloxy)-des-A-A -gonadiene-S-one. This product was used as such for the next step.

Ultraviolet spectrum (in ethanol):

Step C: Preparation of IO-hydroxymethyl-l3B-methyl- 17(3-(3'-methyl 2' butenyloxy)-des A-A -gonadiene- 5-one.-Under an atmosphere of nitrogen, 2.71 gm. of 10-formyl-13fl-methyl-l7fl-(3'-methyl 2' butenyloxy)- des-A-A -gonadiene-5-one were introduced into 30 cc. of tetrahydrofuran; the mixture was cooled to +5 C. and 2.95 gm. of lithium hydridotri isobutoxyaluminate were added thereto. The whole was stirred for 30 minutes at +5 C., then diluted with water and brought to a pH of 3.5 by addition of acetic acid. The aqueous layer was extracted with diethyl ether. The extracts were first washed with an aqueous solution of sodium chloride, then with an aqueous solution of sodium bicarbonate and again with the solution of sodium chloride. The extracts were then dried and evaporated to dryness. The residue was chromatographed over silica gel to afford 1.35 g. of IO-hydroxymethyl-13p-methy1-17fi- (3-methyl 2 butenyloxy)- des-A-A -gonadiene-S-one.

Ultraviolet spectrum (in ethanol): A at 287 to 288 m e==19,960.

This compound is not described in the literature.

The preceding specific embodiments are illustrative of the invention. It is to be understood, however, that other expedients known to those skilled in the art, particularly utilizing the reactions involved on materials having an ethyl or an n-propyl in the 13/3 position may be employed without departing from the spirit of the invention.

We claim:

1. A substituted des-A steroid of the formula BIO-CH2 wherein R is an alkyl having from 1 to 6 carbon atoms, X is a member selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms selected from the group consisting of saturated and unsaturated aliphatic carboxylic acids, saturated and unsaturated cycloaliphatic carboxylic acids, benzoic acid, cycloalkylalkanoic acids, phenylalkanoic acids, phenoxyalkanoic acids, furan-Z- carboxylic acid, 5-t.-butylfuran-2-carboxylic acid and ,8- ketoalkanoic acids.

2. The substituted des-A steroid of claim 1 wherein said R, an alkyl having from 1 to 6 carbon atoms, is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

3. The substituted des-A steroid of claim 1 wherein R is methyl and X is benzoyl.

4. The substituted des-A steroid of claim 1 wherein R is ethyl and X is benzoyl.

5. The substituted des-A steroid of claim 1 wherein R is methyl and X is 2'-methylallyl.

6. The substituted des-A steroid of claim 1 wherein R is methyl and X is 3'-methyl-2'-butenyl.

wherein R is an alkyl having 1 to 6 carbon atoms, X is a member selected from the group consisting of alkylthioalkyl having from 2 to carbon atoms, cycloalkyl having from 4 to 7 carbon atoms, cycloalkylalkyl having from 4 to 11 carbon atoms, and phenylalkyl having from 7 to 11 carbon atoms.

8. The substituted des-A steroid of claim 7 wherein R is methyl and X is benzyl.

9. The substituted des-A- steriod of claim 7 where R is methyl and X is hexahydrobenzyl.

10. The process for the production of a substituted des- A steroid of claim 1 which comprises the steps of formylating a des-A-A -gonene of the formula wherein R is an alkyl having from 1 to 6 carbon atoms, X is a member selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms selected from the group consisting of saturated and unsaturated aliphatic carboxylic acid, saturated and unsaturated cycloaliphatic carboxylic acids, benzoic acid, cycloalkylalkanoic acids, phenylalkanoic acids, phenoxyalkanoic acids, furan-Z-carboxylic acid, 5-t.-butylfuran-Z-carboxylic acid and fit-ketoalkanoic acids, by the action of a formylating agent consisting of an N,N-di substituted formamide and an inorganic chlorination agent dehydrogenating the resulting IO-hydroxymethylene enone of the formula HO-CH wherein R and X have the above-assigned meanings, by the action of a dehydrogenating agent selected from the group consisting of halo-substituted p-benzoquinones, cyano-substituted p-benzoquinones and halo-cyano-substituted p-benzoquinones, reducing the resulting formyl dienone of the formula wherein R and X have the above-assigned meanings, by the action of a metal hydride selected from the group consisting of an alkali metal borohydride and tri-t-butoxyaluminum-lithium hydride in the presence of a solvent media, and recovering said substituted des-A steroid.

11. The process of claim 10 wherein said N,N-disubstituted formamide is a member selected from the group consisting of dimethylformamide, N-methyl-N-phenylformamide and N-piperidino-N-methylformamide.

12. The process of claim 10 wherein said formylating step is eifected by the action of the phosphorus oxychloride-dimethylformamide complex.

13. The process of claim 10 wherein said dehydrogenating agent is' selected from the group consisting of 2,3 dichloro-5,6-dicyano-p-benzoquinone, 2,3-dibromo- 5,6 dicyano p-benzoquinone, 2,3-dibromo-5,6-dicyanop benzoquinone, 2,3,5,6 tetrachloro-p-benzoquinone, 2,3 dicyano -chloro-p-benzoquinone and 2,3-dicyanop-benzoquinone.

14. The process of claim wherein said reducing step is effected by the action of an alkali metal borohydride selected from the group consisting of sodium borohydride and potassium borohydride.

15. The process for the production of a 17-ether des-A steriod of claim 1 which comprises the steps of formy:

lating a des-AA -g0nene of the formula HO-CH= O acyl wherein'R and'acyl havethe above-assigned meanings, by

the action of a dehydrogenating agent selected from the group consisting of halo-substituted p-benzoquinones, cyano-substituted p-benzoquinones and halo-cyano-substituted p-benzoquinones, reacting the resulting formyl dieneon of the formula B0 y H 0=(5 wherein R and acyl have the above-assigned meanings, with a ketalizing agent selected from the group consisting of 2-di-Iower alkyl-dioxolanes and lower alkanediols, saponifying the resulting diketal of the formula wherein R and acyl have the above-assigned meanings and K represents lower alkylenedioxy, etherifying the resulting -01 of the formula wherein R and K have the above-assigned meanings, by the action of a halide of the formula X Hal V wherein Hal represents a halogen other than fluorine and X is selected from the group consisting of alkylthioalkyl having from 2 to 5 carbon atoms, cycloalkyl having from 4 to 7 carbon atoms, cycloalkylalkyl having from 4 to 11 carbon atoms, and phenylalkyl having from 7 to 11 carbon atoms in the presence of a metal hydride and a polar solvent, hydrolyzing the resulting 17-ether of the formula /\R /0X1 t l 1 K:

wherein R, X and have the above-assigned meanings, by

the action of an aqueous organic acid, reducing the resulting formyl dienone of the formula wherein R and X have the above-assigned meanings, by the action of a mixed metal hydride selected from the group consisting of an alkali metal borohydride and tri-t.- butoxy-aluminum-lithium hydride in the presenceof a solvent media, and recovering said l7-ether des-A steriod.

References Cited FOREIGN PATENTS 1,476,631 4/1967 France 260588 LORRAINE A. WEINBERGER, Primary Examiner US. Cl. X.R.

260347.5, 468 R, 468 L, 473 G, 483, 486 R, 488 B, 586 A, 590

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3,766,248 October 16, 1973 Patent No. Dated Inventor) Lucien Nedelec et a1 It is certified thaterror appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 12, The claim of priority should read as follows:

France P.V. 43,565 December 23-, 1965 France P.V. 116,922 I August 4, 1967 France P. V'. 117 ,736 August 11 1967 Column 1,1ine 55, "Reference to Prior Applications" should read This application is a continuation-in-part of our copending applications Serial No. 603,094, filed December 20, 1966, now abandoned, and Serial No 728 ,880, filed May 14, 1968,, now U. S. Patent'No. 3,574,688, this later application being a continuationin-part-of Serial No. 603,457, filed December 21, 1966 and now abandoned. Column 8 line 8, Formula VII should appear as shown below:

' R 0 Acyl I; LI/

Column 9, line 57, "a-A should read A-A (1.11)

Column 14 lines-23 and 24, "atmospheric" should atmosphere line 36, "nirtogen" should read nitrogen Column 16,

line 5 "-reS-" should. read -des- FORM PO-1050 (10-69) v v i u'scomboc 5 v i U. S. GOVERI HENT PRINTING OFFICI I... 0-3..8,

' UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION v 3,766 ,248 Dated October 16, 1973 Patent No.

Inventor) Luc1en Nedelec et a1.

It is certified that error appears in the above-identified patent aqd that said Letters Patent are hereby corrected as shown below.

Column 19', lines 4 and S, cancel "2,Z-dibromo-S,6 dicyanop-benzoquinone"; line 16 the formula in claim 15, should appear as shown be1oy R --'-W a O Acyl a line 49, "'dienon" should read 'r-f dienone Signed arid sealed this 24th day of September 1974.

Attest McCOY M, cnasou JR. c. MARSHALL DANN Attes ting Of f icer Commiss ioner of Patents UsCOMM-DC 0O876-P69 a u. s. covnuuimrlmmus omc: nu o-su-su) FORM P0 1050 (10-69)