3,231,567 United States Patent Office Patented Jan. 25, 1966

2 droxy ethylene, hydroxy propylene, hydroxybutylene and 3,231,567 PROCESS FOR THE PREPARATION OF 3-HY the like; a saturated or unsaturated cycloaliphatic moiety, DROXY. AND 3-ALKOXY-ESTRATRIENES such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, AND INTERMEDIATES THEREFOR cyclopentenyl, cyclohexenyl, cyclopentylpropyl, cyclo Alberto Ercoli and Rinaldo Gardi, Milan, and Cesare 5 heptyl, cyclooctyl radical; or an araliphatic moiety, such Pedrai, Bergamo, Italy, assignors to Francesco Wismara as benzyl, phenetyl, cynnamyl radical. Preferred hydro S.p.A., Casadenovo, Italy carbon radicals are aliphatic moieties containing from 1 No Drawing. Fied Dec. 16, 1963, Ser. No. 330,584 to 8 carbon atoms, inclusive, cycloaliphatic moieties con Claims priority, application Italy, Dec. 19, 1962, taining from 5 to 6 carbon atoms in the ring and the Patent 24,856/62 benzyl radical. 20 Claims. (C. 260-239.55) 10 Methods for the aromatization of the ring A of 19-nor This invention relates to an improved process for con are already known in the literature and the prior verting steroids of the 19-nor- and 19-nor-preg art teaches the conversion of a 3-keto-19-norsteroid of name series into derivatives of the estrogenic series. The the androstane series into a derivative of the estrogenic invention also relates to certain new 19-norsteroid deriva 5 series. This conversion may be accomplished by first tives useful as intermediates in said conversion. preparing a 5,10-epoxy-estren-3-one or a 3-ketal thereof More particularly, this invention is concerned with a by epoxiding a 5 (10)-estrene-3-one or A-3-keto-19-nor amethod for the aromatization of the ring A to produce 3-ketal, respectively, with a peracid. The result 3-hydroxy-1,3,5(10)-estratrienes and ethers thereof rep ing 5,10-epoxy-estren-3-one or 3-ketal thereof is then con resented by the following formulas: 20 verted to the same 103-hydroxy-4-estren-3-one by treat ment with an alkali and the intermediate 108-hydroxy CH compound is finally aromatized with acids to give a phe nolsteroid (Journal Org. Chem, 23, 1744; 1958). Thus, according to the prior art, the aromatization of 25 the ring A is accomplished by a two step process through the intermediate 103-hydroxy-4-estren-3-one. It is also known that ethers of a 3-phenolsteroid are in their turn obtained from the phenolsteroid itself by treatment with OH a hydrocarbon halide. We have now found that g,y-epoxy derivatives of and 30 3-keto-19-norsteroids and 3-ketals thereof can be directly CE converted, by one step only, to 3-hydroxy 1,3,5 (10)-estra trienes when reacted with a strong acid in solution of an inert, non alcoholic organic solvent. 35 We have further found that ethers of 3-hydroxy-13, / 5 (10)-estratrienes can be also obtained from g;y-epoxy derivatives of 3-keto-19-norsteroids and 3-ketals thereof RO by one step only, when the treatment of said epoxy-19 (II) nor-compounds with a strong acid is carried out in the 40 presence of an alcohol. in which R is a hydrocarbon radical and X is a member The 8,y-epoxy compounds which directly aromatize to selected from the group consisting of the following group give phenolsteroids or ethers according to the procedures ings: of the present invention are 5,6-epoxy 3-keto-19-nor O OE OE OH steroids, 5,10-epoxy 3-keto-19-norsteroids and 3-ketals of , C-E, C-lower alkyl, C-lower alkynyl 45 said 5,6 and 5,10-epoxy 3-keto compounds. / N / N / N / N The 56 or 5,10-epoxy compounds may be employed CH3 either in c or in 3-form. (H, (H, Instead of employing a 50,6a- or a 56,66-epoxy deriva go go do tive alone, one may employ mixtures of said isomers or C--OH, d-oAcyl 50 also mixtures of the corresponding 5,6- and 5,10-epoxy / N derivatives, that is a 5,6-epoxy 3-keto-19-norsteroid to The term “lower alkyl" is represented by methyl, ethyl, gether with the corresponding 5,10-epoxy compound or a propyl and butyl radicals; the term "lower alkynyl' in 5,6-epoxy 3-keto-19-norsteroid 3-ketal in admixture with cludes ethynyl, propynyl and butynyl, and Acyl repre the 3-ketal of the corresponding 5,10-epoxy derivative. sents the acyl radical of a hydrocarbon carboxylic acid 55 According to the present invention, opening of the containing from 1 to 4 carbon atoms, the acetyl radical oxido ring dehydration and rearrangement simultane being preferred. ously occur by treatment of the By-epoxy compounds The term “hydrocarbon radical' used for R indicates. with a strong mineral or organic acid in an appropriate a saturated or unsatuated, straight or branched, aliphatic organic solvent to give phenolsteroids or ethers, these moiety containing from 1 to 18 carbon atoms, such as 60 latter if the organic solvent used in the reaction consists methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. bul of or contains an alcohol reagent. tyl, amyl, hexyl, heptyl, nonyl, decyl, dodecyl, miristy, The invention thus provides a general method for the cetyl, stearyl, allyl, crotyl propargyl, cytronellyl group; aromatization of the ring A of the steroid nucleus through a hydroxy substituted lower alkylene group such as hy - B,y-epoxy-3-keto-19-norsteroids. 3,231,567 3 4 The invention also provides new and useful inter of the solventor of the solvent mixture employed; pref mediates in said method for the preparation of phenol erably the reaction is carried out by heating to reflux the steroids, particularly of and its ethers and of 3 reaction mixture for a period of time varying from about hydroxy-176-acetyl-1,3,5 (10)-estratriene and its ethers. ten minutes to about four hours. The 6,y-epoxy-3-keto compounds used for the process of 5 At the end of the reaction the desired estratriene sepa this invention, may be represented by the following gen rates. As said above, by operating in non alcoholic sol eral formulas: vents there are obtained 3-hydroxy-1,3, 5 (10)-estra trienes, while by operating in the presence of an alcohol CEs. or by using an alcohol as sole reaction solvent there are X1 obtained ethers of 3-hydroxy-1,3,5(10)-estratrienes, in: / O which the etherifying group corresponds to the hydro ‘carbon moiety of the alcohol employed. H. The 6,y-epoxy-3-keto compounds of the general Formu / las III and IV, used as intermediates in the process of this 15. invention, are obtained by treating the corresponding 19 Z. nor-compounds, A(56) or A5(10)-unsaturated, with a per acid, under the usual conditions for epoxide formation. O (III) Peracids employed are: performic acid, peracetic acid, perbenzoic acid, monoperphthalic acid or hydrogen' 20. peroxide. The epoxy compounds obtained at the end of the re action consists in general of a mixture of ox and (3 epimers which can be separated according to known methods, i.e., by chromatography. 25 If as starting material for the epoxidation there is em ployed the total crude reaction product obtained by (IV) ketalization of a 19-nor-A-3-ketone, consisting of a mix ture of 19-nor-A5(6)-3-keto 3-ethylene ketal and 19-nor wherein the epoxy group may have either the o- or g A5(10)-3-keto 3-ethylene ketal, there is produced upon . configuration, Z represents ketonic oxygen or a lower 30 epoxidation two isomeric epoxides that is 5, 6- and 5, 10 alkylene ketal and Xi represents a member selected from epoxides, which mixture can be directly employed for the the group consisting of the following groupings: aromatization step according to the invention or can be previously separated in its components by chromato Z oH oH. OE. graphy followed by fractional crystallization. In practice, 35 however, it is more convenient to carry out the aromatiza 8. est, lower alkyl, tower alynyl tion step on the mixture of the epoxides itself, without - CH C CH3 further purification. New and advantageous intermediates for the process d=z (= d-z of this invention are those having the formulas: d-H, -. OH, d-oAcyl 40 / N / N - / N CH3 CEhs in which Z and Acyl are as defined above. The term X2 X2 "lower alkylene ketal" is used herein to indicate ketal derivatives with lower aliphatic glycols, such as ethylene glycol, 1, 2-propylene glycol, 1,3-propylene glycol, 1, 2 45 O butylene glycol, 1,3-butylene glycol and the like. Pre- ... ferred ketal group is ethylene glycol. ketal. The strong acids which can be employed in the process of this invention are mineral acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, 50 (CO pyrophosphoric acid, iodic acid; or strong organic acids such as dichloroacetic acid, trichloroacetic acid, in which X2 represents a cycloethylenedioxy methylene oxalic acid, arylsulfonic acids and the like. Acids which group or a group. have a pK less than 1.5 are considered strong acids for the process of this invention and any of these may be em 55 ployed free of water or in concentrated or diluted aqueous solution. The amount of the acid used is not critical; a catalytic amount is sufficient to carry out the aromatiza tion, but a molecular amount or an excess may be used without damage. 60 The organic, non alcoholic solvents which are employed for the aromatization step in order to obtain phenolster and the C- and/or g-epimers corresponding to the said oids can be selected from benzene, toluene, hexane, cyclo epoxides, such as 5oz, 10oz-oxido-19-nor-androstane-3,17 hexane and other hydrocarbons, acetone, dioxane, tetra dione 3,17-bis(ethylene ketal); 56,108-oxido-19-nor hydrofuran or halogenated organic solvents, such as 65 androstane-3,17-dione 3,17-bis (ethylene ketal); 5oz,6oz methylene chloride, chlorobenzene, chloroform and car oxido-19-nor-androstane-3,17-dione 3, 17 - bis(ethylene bon, tetrachloride; preferred non alcoholic solvent is ace ketal) and 5p3,103,oxido-19 nor -3,20-dione 3,20 tone...... - bis(ethylene ketal). Upon short heating with acids, the For the preparation of phenolethers according to the above intermediate epoxides aromatize in very good yield, invention, the reaction is carried out in the presence of 70 with simultaneous hydrolysis of the ketal groups at the an alcohol of the formula ROH, in which R has the 17- or 20-position, to give the corresponding phenol meaning defined above, or by using an alcohol of the steroids,o or phenolethers according to the process of this. formula ROH as sole reaction solvent. - invention...... The aromatization step can be performed at tempera The advantage in using the above intermediates is given tures between the room temperature and the boiling point. by the fact that the ketals of A5(6) and A5(10)-3-keto-19 s 3,231,56 - 6 horsteroids, from which the said 5,6 and 5,10-epoxides A solution of 2.1 g of 10-cyano-19-nor-5-androstene are produced, are now easily available by means of a new 3,3,176-diol in 100 cc. of dry acetone is reacted under method recently developed and fully described in our U.S. nitrogen atmosphere and at room temperature with 5 cc. copending applications Serial No. 228,242, filed on Oc of an 8 N solution of chromic acid (prepared by treat tober 4, 1962, now patent No. 3,154,469, and Serial No. ing 26.7 g. of chromium trioxide with 23 cc. of concen 279,304 filed on May 9, 1963. According to this method, trated sulfuric acid and by diluting the resulting mixture the above ketals are produced by direct synthesis from with distilled water to 100 cc.). The reaction mixture is the derivatives of the normal series through the corres stirred under nitrogen atmosphere for 5 minutes, then ponding 106-cyano-19-norsteroids. poured into ice-water saturated with sodium chloride and The following examples are illustrative of the products O extracted with either. The ethereal solution is washed and methods of this invention, but are not to be con with water, dried over sodium sulfate and the ether evapo strued as limiting. rated to give 1.35g. of 10-cyano-19-nor-5-androstene-3,17 dione, M.P. 152-156° C.; al= -69 (chl. 0.5%). PREPARATION 1-19 - NOR - 5(6)-ANDROSTENE To a solution of 840 mg. of the latter compound in 75 3,17-DIONE 3,17-BIS(ETHYLENE KETAL) AND cc. of benzene is added 5 cc. of ethylene glycol contain 19-(NOR-5 (10) ANDROSTENE - 3, 17 - DIONE 3,17 ing 50 mg. of p-toluenesulfonic acid. The mixture is BIS(ETHYLENE KETAL) refluxed for 15 hours in the absence of moisture, then it is neutralized with a few drops of pyridine and concen A solution of 2.4 g of the 36,176-diacetoxy-5a-andro trated under vacuum. The residue, recrystallized from stane-6-one (prepared by acetylation with acetic anhy 20 methanol, gives 785 mg. of 10-cyano-19-nor-5-andro dride of the corresponding 3,3,17f8-dihydroxy compound) stene-3,17-dione 3,17-bis(ethylene ketal), M.P. 211-212 in 62 cc. of tetrahydrofuran and 6.2 cc. of water is treated C.; o?4= -133° (chl. 0.5%). under stirring with 600 mg. of sodium borohydride at 850 mg. of the compound are dissolved in 350 cc. of room temperature for 4 hours. The excess of sodium boiling absolute ethanol and treated with 20 g. of sodium borohydride is then decomposed by the addition of dilute 25 metal added little by little in the course of 2 hours. A acetic acid, the mixture poured into ice-water and the portion of the alcohol is then distilled off and the re precipitate formed is collected by filtration, washed with maining solution is cautiously diluted with water, while water and dried under vacuum, thus giving 2 g. of 3,17 the temperature is maintained around 0° C. by cooling diacetate of 5cy-androstane-36,66,176-triol. The product with ice. The mixture is extracted thoroughly with ether; recrystallized from dilute methanol melts at 130-131 C.; 30 the combined extracts are washed with water, dried and ox27=-30-1 (chl. 0.5%). . the solvent evaporated to give a mixture of A5(6) and To a solution of 1.2 g. of the diacetate of 5c-andro A5(10) isomers of 19-nor-androstene-3,17-dione 3,17 stane-36,66,176-triol in 20 cc. of dry pyridine, cooled to bis(ethylene ketal). -5 C., 1.6 cc. of notrosyl chloride is added dropwise with Example I stirring. Stirring is continued for 4 hours and the tem 35 perature maintained at -5° C.; the mixture is then 2 g. of the total residue obtained in Preparation 1, poured into ice-water to precipitate the 5a-androstane consisting of a mixture of 19-nor-5 (6)-androstene-3,17 36,176-diacetoxy-63-yl nitrite which is collected, washed dione 3,17-bis(ethylene ketal) and 19-nor-5 (10)-andro with water and dried (yield 1.1 g.). After recrystalliza stene 3,17 - bis(ethylene ketal), is dissolved in tion from hexane-benzene the product melts at 152-153 40 200 cc. of ether and treated at 5° C. with 20 cc. of a 15% C. (dec.); or 27- -55-1 (chl. 0.5%). ether solution of monoperphthalic acid. After standing A solution of 5.8 g. of the nitrite in 100 cc. of dry overnight at room temperature, the etheral solution is toluene in a Pyrex vessel is irradiated by means of a 200 washed with a 5% sodium carbonate solution, a saturated watt mercury arc lamp for 3 hours at a temperature of aqueous solution of sodium chloride and water, then about 15° C., while a stream of dry nitrogen free from dried and concentrated under vacuum to dryness. The oxygen is passed into the vessel. During the photolysis 45 residue (about 2 g.) consists of a mixture of 5,6- and the solution becomes turbid because the oximino deriva 5,10-oxides of 19-nor-androstane-3,17-dione 3,17-bis tive, which formed, separates. The solid material is then (ethylene ketal). filtered, washed with toluene, dried and recrystallized The mixture of 5,6- and 5,10-oxides thus produced may from benzene to give 3.2 g. of the nitroso-dimer cor be used without further purification for the aromatiza responding to the 19-oximino-5a-androstane-3,3,66,17f8 tion step. It is possible however to separate the isomeric triol-3,17-diacetate melting at 162-163 C.; epoxides by chromatography over activated magnesium silicate (Florisil). Elution with benzene-ether (3:2) Io.27= -79-1 (chl. 0.5%) gives the 5,10-oxide. A solution of 1.7 g. of the nitroso-dimer is 50 cc. of dry Recrystallization of the 5,10-oxido compound from pyridine is treated, at a temperature around 0°C., by methanol provides the 3-epoxy compound, 58,106-epoxy dropwise addition with 10 cc. of phosphorus oxychloride. 19-nor-androstane-3,17-dione 3,17-bis(ethylene ketal), The reaction mixture is stirred at room temperature (yield 1.35 g.). A second recrystallization from hexane under anhydrous conditions for 20 hours, then poured affords the pure product, melting at 116-117 C.; into ice-water and extracted with either. The ethereal 60 ox2=-|-10 (chloroform, c. =0.5%). solution is washed with dilute hydrochloric acid and an After evaporation of the methanolic mother liquor and aqueous solution of sodium bicarbonate, successively, then recrystallization of the residue from methanol, there are with water and, after being dried over magnesium Sul obtained 0.1 g of the cy-epoxy compound, 5cc, 10oz-epoxy phate, is concentrated to obtain 1.3 g of 10-cyano-19 19-nor-androstane-3,17-dione 3,17-bis(ethylene ketal), nor-5-androstene-3,6,1713-diol, diacetate. The product 65 melting at 120-121 C.; als---20 (chloroform, melts at 160-161° C. after recrystallization from methyl c.=0.5%). After further elution of the column with alcohol; c.27=-166-2 (chl. 0.5%). The com benzene-ether (1:1) there is obtained the 5c,6a-oxido pound dissolved in 40 cc. of ethanol is heated to reflux compound, 5c,6a-epoxy-19-nor-androstane - 3,17-dione for 3 hours with 10 cc. of 2 N aqueous potassium hy 3,17-bis(ethylene ketal) (yield 0.37 g.). The pure droxide solution. 70 product melts at 190-191 C.; (olp25- -41 (chloroform, After cooling, the alcohol is removed and water is c.=0.5%). added to precipitate the 10-cyano-19-nor-5-androstene Example 2 36,176-diol which is collected, washed with water, dried and recrystallized from ethanol. M.P. 209-210 C.; 1 g. of 56,108-oxio-19-nor-androstane-3,17-dione 3,17 ox25=-174 (dioxane). 75 bis(ethylene ketal), obtained as described in Example 1, 3,231,567 7 8 is dissolved in 5 cc. of acetone and heated to reflux for pentanol and treated with 2 drops of concentrated hydro 2 hours with two drops of concentrated hydrochloric chloric acid. The reaction mixture is heated for 1 hour acid. The solution is evaporated under reduced pressure, on boiling water bath and the alcohol in excess is evapo the residue is diluted with water and the crystalline precipi rated under reduced pressure. The residue is taken up tate is filtered, washed with water and dried. There are with methanol and filtered. There are obtained 42 mg. obtained 0.580 g. of estrone melting at 253-255 C. The of estrone cyclopentyl ether, melting at 152-153 C.; melting point is undepressed with an authentic sample of a 25- --136 (dioxane, c.=0.5%). eStrone. - By operating as described above but employing, as Example 3 alcohol reagent, cyclohexanol, benzyl alcohol or cyclo 10 pentyl-propanol, instead of cyclopentyl alcohol, there are 100 mg. of 5oz,10a-oxido-19-nor-androstane-3,17-dione obtained estrone cyclohexyl ether, M.P. 156-157° C.; 3,17-bis(ethylene ketal), obtained as described in Ex del 26= --134 (dioxane, c.=0.3%), estrone benzyl ample. 1, is heated to reflux for 1 hour in an acetone ether, M.P. 129-130 C.; ox25=-132 (dioxane, solution containing two drops of 40% sulfuric acid to c.=0.5%) and estrone cyclopentyl propyl ether, respec give estrone, M.P. 254-255 C. The melting point is un 15 tively. depressed with an authentic sample of estrone. Example 10 Example 4 100 mg. of 56,108-oxido-19-nor-androstane-17a-methyl 100 mg. of 50,6a-oxido-19-nor-androstane-3,17-dione 176-ol-3-one 3-ethylene ketal (prepared as described in 3,17-bis-(ethylene ketal), obtained as described in Ex 20 J.A.C.S., 81, 3120; 1959) is dissolved in 15 cc. of hexane ample 1, are dissolved in 5 cc. of acetone and 2 cc. of i and treated on boiling water bath with 0.5 cc. of tri methyl alcohol. Traces of concentrated hydrochloric acid chloroacetic acid. After evaporation of the solvent and are added and the solution is heated to reflux for about dilution with water, there is obtained 55 mg. of 17a thirty minutes. The reaction mixture is then concen methyl , melting at 185-187 C. The procedure trated under vacuum and the residue extracted with ether. 25 of Example 9 is applied to the starting material of this The ether solution is dried over magnesium sulfate, example to produce 3-cyclopentyl ether of 17 oz-methyl filtered and concentrated to dryness to give estrone methyl estradiol, M.P. 107-108. C.; al?= -45 (dioxane, ether melting at 169-170° C.; oD=-162 (chloro c.=0.5%). - - - - form). Example II Example 5 30 2 g. of the mixture of 5,10- and 5,6-oxido compounds The mixture of 5,6- and 5,10-oxides obtained as total obtained in Preparation 1 is dissolved in 100 cc. of ace residue in Example 1 (about 2 g) containing 5,6-epoxy- . tone. containing 8 g. of cetyl alcohol. The solution is re 19-nor-androstane-3,17-dione 3,17-bis(ethylene ketal) and fluxed for 2 hours with 1.5 cc. of perchloric acid to give 5,10-epoxy-19-nor-androstane-3,17-dione 3,17-bis(ethyl estrone cetyl ether, melting at 67-68 C.; as --95 ene ketal), is dissolved without further purification in 35 (dioxane, c.=1%). 20 cc. of acetone and the solution heated to reflux for By Substituting a corresponding amount of n-nonyl alco about 2 hours with 0.3 cc. of concentrated hydrochloric hol for cetyl alcohol, there is obtained estrone n-nonyl acid. The mixture is then cooled and diluted with water ether, M.P. 56-58 C.; c.125=-|-114 . (dioxane, and the product which precipitates is recovered by filtra 40 c.-:1% ). tion. By recrystallization from acetone there is obtained Similarly, by reacting the starting material of this ex pure estrone, melting at 258-260 C. ample with the appropriate alcohol in the presence of an acid, such as those named above, there are produced Example 6 other estrone ethers as, for example, the n. hexyl ether, A solution of 1.2g.of 19-nor-5 (10)-androstene-3,17 - M.P. 75-76 C.; a)25=-|-128.5 (dioxane, c.--0.5%), dione in 100 cc. of ether is treated at room temperature 45 the (2 - methyl) - pentyl ether, M.P. 74-75 C.; with 10 cc. of 15% ether solution of monoperphthalic op=--139.3 (dioxane, c.- 0.6%), the n. octyl ether, acid to give 800 mg. of 56,106-epoxy-19-nor-androstane M.P. 62-63 C.; ox?---122 (dioxane, c.-0.5%), 3,17-dione, melting at 143-145 C. The 5,10-oxido com the n. decyl ether, M.P. 56-58 C.; c.25---120.5 pound (100 mg.), dissolved in 5 cc. of acetone is treated 50 (dioxane, c.=1%), the lauryl ether, M.P. 63-65 C.; with two drops of concentrated hydrochloric acid and the IoID=-|-101 (dioxane, c.=1%), myristyl ether, M.P. mixture heated to reflux for 1 hour. After cooling, the . . 59-61. C.; c.jp25---100 (dioxane, c.-1%), allyl solution is concentrated under vacuum and the crystal ether, M.P. 107-108 C.; o25=-|-144 (dioxane, line residue taken up with little aqueous acetone to give . c. = 1%), cinnamyl ether, M.P. 144-145 C. 81 mg. of estrone melting at 256-2.58 C. 55 PREPARATION 2-19 - NOR-5(6)-PREGNENE-320 Example 7 DIONE 3,20-BIS(ETHYLENE KETAL) AND 19 NOR-5 (10)-PREGNENE - 3,20,. - DIONE 320 - BIS 1. g. of 5p, 106-oxido-19-nor-androstane-17B-ol-3-one (ETHYLENE KETAL) (prepared as described in J. Org. Chem., 23, 1744; 1958) is treated according to the procedure of Example 2 with 60 To a solution of 11.3 g. of the 3,20-diacetate of 5 hydrochloric acid in acetone solution to give 700 mg. of pregnane-36,203-diol-6-one in 110 cc. of tetrahydrofuran estradiol, M.P. 173-175 C. is added dropwise under stirring 45 cc. of an aqueous solution containing 1.1 g of sodium borohydride. Stir Example 8 ring is continued for 8 hours at room temperature and 65 then the excess of sodium borohydride is decomposed by 1 g. of the starting material of Example 5 is treated addition of dilute acetic acid. By pouring the mixture with 100 mg. of p-toluenesulfonic acid in 30 cc. of boil into ice-water a precipitate is formed which is filtered, ing ethanol for fifty minutes. The alcohol is then re washed with water and dried. There is thus obtained 8 g. moved under reduced pressure and the crude residue is of the diacetate of 5a-pregnane-36,66,206-triol. The diluted with water-to give a precipitate of estrone 3-ethyl 70 product recrystallized from hexane shows melting point ether melting at 126 C.; op=-|-150 (dioxane). 169-171° C.; old?= +3° (chloroform, c. =0.5%). Example 9 The above compound (5.2 g.) is dissolved in 30 cc. of dry pyridine, cooled at -5° C. and treated little by little 100 mg. of 59,106-oxido-19-nor-androstane-3,17-dione with 2 cc. of nitrosyl chloride, with stirring while main 3,17-bis(ethylene ketal) are dissolved in 5 cc. of cyclo 75 taining the temperature. around -5°C. After a further 3,231,567 9 10 4 hours at -5° C. the mixture is poured into ice-water chloric acid. The solution is then evaporated under re until complete precipitation of the product which is fil duced pressure and the residue diluted with water to give tered and dried thus giving 5.2 g. of 36,203-diacetoxy-5a 0.6 g. of 3-hydroxy-17f8-acetyl-1,3,5(10)-estratriene, melt pregnane-63-yl nitrite. Recrystallization from methanol ing at 247-249 C.; ol?---159 (chloroform, methylene chloride yields the pure product melting at c.=0.5%). 153-154 C. (dec.); a 25- -35 (chl. 0.5%). Example 13 A solution of 5 g. of the above compound in 100 cc. The 5,10-oxido compound obtained in admixture with of anhydrous toluene is photolyzed in a Pyrex vessel at the corresponding 5,6-oxido compound according to the 10° C. under pure nitrogen, using a Q81 watt high pres procedure of Example 12 is purified by chromatography sure mercury lamp with a Pyrex filter immersed into the O over activated magnesium silicate. Elution with benzene reaction solution. After 3 hours, at the end of the irradi ether (3:2) provides the pure 5,3,103-oxido compound, ation, the precipitate formed is filtered, washed with tolu 5p3,106-epoxy-19-nor-pregnane-3,20-dione 3,20-bis(ethyl ene and dried, thus obtaining 1.45 g. of 36,203-diacetoxy ene ketal), melting at 136-137° C.; alp=-|-58 (chloro 19-nitroso-5a-pregnane-66-ol (dimer) which recrystal form). 1.5 g. of this compound is treated with 50 cc. lized from acetone-hexane melts at 163-164 C.; 15 of methanol and 100 mg. of p-toluenesulfonic acid. The cl25=-43 (chl. 0.5%). By dilution of the mother reaction mixture is heated to reflux for fifty minutes, then liquor with petroleum ether there is obtained 1.2 g. of diluted with water and the product which precipitates 38,203-diacetoxy-19-oximino-5oz-pregnane-66-ol. filtered and recrystallized from methanol to give 3-meth Total yield: 2.65 g. equal to 53%. The pure 19-oxim oxy-176-acetyl-1,3,5(10)-estratriene, melting at 134-136 ino compound, recrystallized from ethyl acetate, shows 20 melting point 218-219 C.; IoI25=-25 (chi. 0.5%). C.; al’=-|-160 (chloroform, c. =0.5%). A mixture of the 19-oximino compound and the ni Example 14 troso-dimer (2 g.), as obtained above, is dissolved in 37 cc. of dry pyridine and treated with 6 cc. of phosphorus 1 g. of 19-nor- 3-ethylene ketal is dissolved oxychloride. The mixture is kept at room temperature 25 in 80 cc. of ether and treated at room temperature with under anhydrous conditions for 15 hours, after which the 5 cc. of a 20% ethereal solution of monoperphthalic product is precipitated by the addition of ice-water and acid to give a mixture of 5,6 and 5,10-oxido compounds collected. There is thus obtained 1.6 g. of 10-cyano-19 which can be separated according to the procedure de nor-5-pregnene-38,203-diol diacetate. scribed in J.A.C.S., 81, 3120; 1959. After recrystallization from methanol-methylene chlo The total crude product is treated with 0.8 cc. of di ride the melting point is 189-190° C.; celD25=-127-1 chloroacetic acid in 15 cc. of hexane solution, under the (chl. 0.5%). conditions described in the preceding examples, and A solution of 1. g. of this compound in 40 cc. of converted to estradiol. methanol is treated to reflux for 2 hours with 10 cc. of aqueous sodium hydroxide solution. By cooling and 35 Example 15 diluting with water there is obtained 700 mg. of 10-cyano 19-nor-pregnene-38,206-diol melting at 272-273° C., after 1 g. of 5g,103-oxidor 19-nor-pregnane-3,20-dione 3,20 a recrystallization from methanol; alD=-180 (chl. bis (ethylene ketal) are dissolved in 15 cc. of cyclopen 0.5%). tanol and treated with 0.5 cc. of concentrated hydro The compound dissolved in dry acetone is treated under 40 chloric acid. The reaction mixture is heated for 1 hour nitrogen atmosphere with 1 cc. of 8 N solution of chromic on boiling water bath and the alcohol in excess is evapo acid to give 10-cyano-19-nor-5-pregnene-3,20-dione, M.P. rated under reduced pressure. The residue is taken up 188-192 C. with methanol and filtered. There is obtained 0.8 g. of 4 g. of this compound is added to a solution of 300 3-cyclopentyloxy-17f8-acetyl-1,3,5(10)-estratriene, melting cc. of anhydrous benzene containing 20 cc. of ethylene 45 at 112-114 C.; ox)=-|-138 (dioxane). glycol and 250 mg. of p-toluenesulfonic acid and the Example 16 mixture refluxed for 15 hours. After neutralization with a few drops of pyridine, the liquid is evaporated under 100 mg. of 19- nor-testosterone 3-propylene ketal vacuum and the residue recrystallized from methanol (obtained by treating 19-nor-testosterone with 1,2- methylene chloride to give 10-cyano-19-nor-5-pregnene 50 propylene glycol in the presence of p-toluenesulfonic 3,20-dione 3,20-bis(ethylene ketal). acid) are dissolved in 5 cc. of ether and treated at 5 C. This compound is treated with sodium metal in ab with 5 cc. of a 15% ethereal solution of peracetic acid solute ethanol in the same manner as shown in Prepara to obtain a mixture of 5,6- and 5,10-oxides of 19-nor tion 1 for the corresponding 10-cyano-19-nor-5-andro androstane-176-ol-3-one 3-propylene ketal. The total stene-3,17-dione 3,17-bis(ethylene ketal). The product 55 crude product is dissolved, without further purification, of the reaction consists of 19-nor-5 (10)-pregnene-3,20 in 5 cc. of n-hexyl alcohol and the solution heated for dione 3,20-bis(ethylene ketal) in admixture with little 19 2 hours on boiling water bath with 2 drops of concen non-5(6)-pregnene-3,20-dione 3,20-bis(ethylene ketal), trated hydrochloric acid to give estradiol n-hexyl ether, melting at 134-140 C. melting at 70-71 C.; alp24=-|-65 (dioxane, 60 c.s. 0.5%). Example 12 PREPARATION 3 2 g. of the product obtained in Preparation 2 are dis solved in 200 cc. of ether and treated at 5° C. with 60 cc. 2 g. of 10-cyano-19-nor-5-androstene-3,6,176-diol, ob of a 15% ethereal solution of monoperphthalic acid. The tained as described in Preparation 1, is treated with 2.5 reaction mixture is allowed to stand overnight at room 65 g. of aluminum ispopropoxide and 25 cc. of cyclohex temperature, then washed with a 5% aqueous Solution of anone in anhydrous toluene solution. The mixture is sodium bicarbonate, a saturated sodium chloride solution heated to reflux for 3 hours, distilling, from time to and with water until neutrality and finally dried and time, little quantities of the solvent. After adding water evaporated under reduced pressure to dryness. The crude acidulated with hydrochloric acid, the toluic layer is residue consists of 5,10-epoxy-19-nor-pregnane-3,20-dione 70 Separated and the mother-liquors are extracted with 3,20-bis(ethylene ketal) in admixtures with traces of 5,6- ether. The organic layers are collected, washed, dried epoxy - 19 - nor-pregnane-3,20-dione 3,20-bis(ethylene and evaporated. From the residue extracted again with ketal). ether, 1.350 g. of 10-cyano-19-nor-A4-androstene-3,17 The crude product is dissolved in 15 cc. of acetone and dione is obtained, which after recrystallization from heated to reflux for 2 hours with 0.5 cc. of dilute hydro 75 methanol melts at 183-185° C. 3,231,567 11 12 1 g. of this product is treated with 20 cc. of 2-methyl is allowed to stand overnight at room temperature, then 2-ethyl dioxolane and 30 mg. of p-toluenesulfonic acid. washed with a 5% aqueous solution of sodium bicar The reaction mixture is heated for about 5 hours, then bonate, a saturated sodium chloride solution and with it is neutralized with sodium carbonate and the benzene water until neutrality and finally dried and evaporated is completely evaporated under vacuum. The residue, under reduced pressure to dryness. The crude residue taken up with dilute methanol, gives 3-ethylenedioxy-10 consists of 5,10-epoxy-17a-acetoxy-19-nor-pregnane-3,20 cyano-19-nor-5-androstene-17-one. 2. g. of the 3-mono dione 3-ethylene ketal in admixture with traces of 5,6- ketal, dissolved in 40 cc. of anhydrous toluene are treated epoxy-17c-acetoxy-19-nor-pregnane-3,20-dione 3-ethylene with potassium t. amylate. A slow stream of purified ketal. The crude product is dissolved in 15 cc. of ace acetylene is bubbled in the solution for 20 hours at room 10. tone and heated to reflux for 2 hours with 0.5 cc. of con temperature after which the reaction mixture is poured centrated hydrochloric acid. The solution is then evapo into a mixture of ice-water containing hydrochloric acid. rated under reduced pressure and the residue diluted with The organic layer is separated and the liquor evaporated water to give 17a-acetoxy-176-acetyl-1,3,5(10)-estratri to give 10-cyano-17 oz-ethynyl-19-nor-5-androstene-173-ol ene-3-ol, melting at 242-244 C.; or D25= --49 (chloro 3-one 3-ethylene - ketal. A solution of 10-cyano-3- 5 form, c. = 0.5%). , monoketal in 60 cc. of dry ether and 60 cc. of dry Example 20 dioxane is dropped into 400 cc. of liquid ammonia. 1 g. of 17 cc-hydroxy-19-nor- 3.20-bis(ethyl Then 1.2 g. of lithium in small pieces are introduced. ene ketal) (obtained by heating 17a-hydroxy-19-nor over a period of 90 minutes and the mixture is main progesterone for 15 hours at reflux with ethylene glycol tained under stirring until the blue color of the solution 20 in the presence of benzenesulfonic acid), is dissolved in is discharged. 10 g. of ammonium chloride are added 50 cc. of ether and treated at 5°C. with 15 cc. of a 15% and the stirring is continued for some hours longer at ethereal solution of perbenzoic acid. The reaction mix room temperature. Most of the ammonia is evaporated ture is allowed to stand overnight at room temperature, cautiously, maintaining the mixture on a water-bath and then washed with a 5% aqueous solution of sodium bi diluting the resulting solution with water. After re 25 carbonate, a saturated sodium chloride solution and with peated extractions with ether, an oily residue is obtained water until neutrality, then dried and evaporated under consisting of a mixture of A5(6) and A5(10) isomers of vacuum to dryness. The crude residue consists of 5,10 17 oz-ethynyl-19-nor - androstene-176-ol-3-one 3-ethylene epoxy - 19-nor-pregnane-17a-ol-3,20-dione 3,20-bis(ethyl ketal. ene ketal) in admixture with traces of 5,6-epoxy-19-nor Example 17 30 pregnane-17 oz-ol-3,20-dione 3,20-bis(ethylene ketal). 1.5 g. of the total crude product obtained in Prepara The crude product is dissolved in 15 cc. of acetone and tion 3 is dissolved in 150 cc. of ether and treated with 10 heated to reflux for 2 hours with 0.5 cc. of sulfuric acid. cc. of a 20% ethereal solution of perbenzoic acid. The solution is then evaporated under reduced pressure The mixture is allowed to stand overnight at room and the residue diluted with water to give 176-acetyl temperature, then washed with a 5% solution of sodium 1,3,5(10)-estratriene-3,17a-diol, melting at 240-242 C.; bicarbonate, a saturated solution of sodium chloride and a JD25= --90.5 (dioxane). finally with water until neutrality. The dried solution Example 2I is evaporated under reduced pressure and the residue is The 5,10-oxido compound obtained in admixture with taken up with a mixture of methylene chloride-methanol 40 the corresponding 5,6-oxido derivative, according to the to obtain a mixture of 5,6- and 5,10-epoxides of 17a procedure of Example. 20, is purified by recrystallization ethynyl-19-nor-androstane-17(3-ol-3-one 3-ethylene ketal from methanol to give 5,3,106-epoxy-19-nor-pregnane-17a more precisely 5oz,6cy and 56,106-oxides. - ol-3,20-dione 3,20-bis(ethylene ketal). The mixture of isomeric epoxides is dissolved in .50 1 g. of this compound is treated with 50 cc. of meth cc. of benzene and 10 cc. of cyclopentanol and heated to anol and 100 mg. of p-toluenesulfonic acid. The reaction reflux with 80 mg. of benzenesulfonic acid. After cool mixture is heated to reflux for 30 minutes, then diluted ing, the reaction mixture is diluted with water and the with water and the product which precipitates is filtered precipitate thus obtained is collected by filtration, to give and recrystallized from methanol to give 3-methoxy-176 the 3-cyclopentyl ether of the 17a-ethynyl-estradiol, acetyl-1,3,5(10)-estratriene-17a-ol, melting at 150-152° melting at 107-108 C.; a 25---5 (dioxane, 50 c.-0.5%). C.; a)25=-45.5 (dioxane, c. =0.5%). Similarly, by reaction with the appropriate alcohol re We claim: . . : agent, there are produced other 3-ethers of 17 oz-ethynyl 1. In a process for the preparation of phenolsteroids estradiol, such as for example the ethyl, propyl, of the formula: isopropyl, n-butyl, n-amyl, cyclohexyl and benzyl ethers. CH, Example 18 r /XS 17c-ethyl-19-nor-testosterone 3-ethylene ketal is treated with perbenzoic acid according to the procedure of I Example, 17 to produce a mixture of isomeric epoxides 60 (5,6 and 5,10-oxides) of 17o-ethyl-19-nor-androstane 17,3-ol-3-one 3-ethylene ketal. The mixture of the 5,6 and 5,10-oxides thus produced is treated with cyclopenityl wherein X is a member selected from the group consitsing alcohol and benzenesulfonic acid as in the same Example of the following groupings: 17 to obtain 3-cyclopentyl ether of 17 oz-ethylestradiol, 65 OH g M.P. 122-124° C.; op=-43.5 (dioxane). C. , -El, Cy-lower alkyl, C-lower alkynyl /N / N Example 19 GH. C3 CEL3 850 mg. of 17a-acetoxy-19-nor-progesterone-3-ethylene 70 go do do ketal (obtained by treating 17 oz-acetoxy-19-nor-progester C-H, (-OH, d-oAcyl one with ethylene glycol in the presence of p-toluenesul / N / N / N fonic acid under mild conditions) are dissolved in 80 and Acyl represents the acyl radical of a hydrocarbon 'cc. of ether and treated at 5° C. with 5 cc. of a 15% carboxylic acid containing from 1 to 4 carbon atoms, the ethereal solution of monoperphthalic acid. The mixture Step which comprises reacting ag,y-epoxy3-keto-19-nor 3,231,567 3 14 Steroid derivative selected from the group consisting of step which comprises reacting a 5,y-epoxy-3-keto-19-nor (a) a 5,6-epoxide of the formula: steroid derivative of the formula: CH CH X1 X1 5 / / N

H H. ^N/N/ 10 Z= O in which, y X- isa a member selected from the group con 15 sisting of the following groupings: in which X is a member selected from the group con- Z. OH OE. O sisting of the following groupings: y &-H, d-lower alkyl, d-lower allkynyl / N / N / N / N Z. OH OH OH CE3 CE3 CHs C , C.-H., C.--lower alkyl, --lower alkynyl-- 20 p=2-z (=z- q=2 / N / N / N. / N C-H, C--OH, C--O Acyl CH3 CH3 CE3 M N / N / N (-2 &= Z (-z Z is selected from the group consiting of ketonic oxygen 25 and a lower alkylene ketal and Acyl is as defined above, exH, croH,croAcyl with a strong acid selected from the group consisting of mineral and organic acids having a pK less than 1.5 in Solution of an inert, non-alcoholic organic solvent. Z is selected from the group consisting of ketonic oxygen 3. In a process for the preparation of phenolsteroids and a lower alkylene ketal and Acyl is as defined above; 30 of the formula: (b) a 5,10-epoxide of the formula: CH3

CH3 X1 / N "35 /

HO o 40 in which X is a member selected from the group consisting Ze. of the following groupings: pH (pH (pH in which X1 and Z are as defined above; and (c) a mix- - or H, crower alkyl, crlower alkynyl ture of said corresponding 5,6 and 5,10-epoxides, with a CBI CH3 CH strong acid selected from the group consisting of mineral 45 t and organic acids having a pK less than 1.5 in Solution go o go of an inert, non alcoholic organic solvent. C-H, C--OH, C--O Acyl 2. In a process for the preparation of phenolsteroids / N / N 7 N of the formula: 50 and Acyl represents the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 4 carbon atoms, CH3 the step which comprises reacting a 5,10-epoxy-3-keto /N/X\ 19-norsteroid derivative of the formula: CH 55 XI / / N

60 wherein X is a member selected from the group consist ing of the following groupings: in which X is a member selected from the group con O OH OH. OH 65 sisting of the following groupings: s s 8-H, d-lower aikyi, (-lower alkynyl . QH gh (H ^ N / N / N / N C , C.-H, C-lower alkyl, C-lower alkynyl CH CH3 CF3 N N / N / N 7 N d CE C CH3 O COd CO! - 70 C=Z C=Z CaZ C--i, --OH, C--O Acyl / N / N / C-H, C--OH, C--O Acyl / N / N / N and Acyl represents the acyl radical of a hydrocarbon Z is selected from the group consisting of ketonic oxy carboxylic acid containing from 1 to 4 carbon atoms, the 75 gen and a lower alkylene ketal, and Acyl is as defined 3,231,567 15 16 above, with a strong acid selected from the group con (b) a 5,10-epoxide of the formula: sisting of mineral and organic acids having a pK less than 1.5 in solution of an inert, non alcoholic organic solvent. CE 4. A process as defined in claim 1 in which the strong acid is hydrochloric acid and the non alcoholic organic solvent is acetone. 5. In a process for preparing estrone the step which comprises reacting a member selected from the group consisting of 5,6-epoxy-19-nor-androstane-3,17-dione 3,17 bis(ethylene ketal), 5,10-epoxy - 19-nor-androstane-3,17 10 0. I) dione 3,17-bis(ethylene ketal) and mixtures of said 5,6 and 5,10-epoxy compounds, with a strong acid selected from the group consisting of mineral and organic acids having in which X and Z are as defined above, and a pK less than 1.5 in solution of an inert, non alcoholic (c) a mixture of said corresponding 5,6 and 5,10 organic solvent. epoxides, with a strong acid selected from the group 6. In a process for preparing 17 oz-ethynyl estradio the .5 consisting of mineral and organic acids having a pK step which comprises reacting a member selected from the less than 1.5 in the presence of an alcohol of the for group consisting of 5,6-epoxy-17 oz-ethynyl-19-nor-andro mula ROH, in which R has the meaning defined stane-176-ol-3-one 3-ethylene ketal, 5,10-epoxy-17o-ethy above. nyl-19-nor-androstane-173-ol-3-one 3-ethylene ketal and 20 8. In a process for the preparation of phenolethers of mixtures of said 5,6 and 5,10-epoxy compounds, with a the formula: m strong acid selected from the group consisting of mineral and organic acids having a pK less than 1.5 in solution CH3 of an inert, non alcoholic organic solvent. 7. In a process for the preparation of phenolethers of 25 the formula: /

RO C. in which R is a hydrocarbon radical, X is a member se lected from the group consisting of the following group RO ings: 35 wherein R is a hydrocarbon radical, X is a member se QIt QH pH lected from the group consisting of the following group C , C-E, C--lower alkyl, C-lower alkynyl 1ngS: / N / N / N. N OE gh gh gil, CH3 pH, - C , (-H, C--lower alkyl, C--lower alkynyl 40 go bo o / N 1 N / N /. N. &-H, -on, --OAoyl C CH3 Cs / N / N / N and Acyl represents the acyl radical of a hydrocarbon car C-H,go C--OH,co C--Oco Acyl / N / / N boxylic acid containing from 1 to 4 carbon atoms, the and Acyl represents the acyl radical of a hydrocarbon step which comprises reacting a 5,10-epoxy-3-keto-19-nor carboxylic acid containing from 1 to 4 carbon atoms, the steroid derivative of the formula: step which comprises reacting a 6,y-epoxy-3-keto-19-nor CE steroid derivative selected from the group consisting of 50 (a) a 5,6-epoxide of the formula: X CH X mimiki r / O) in which X1 is a member selected from the group consist 2-- ing of the following groupings: in which X1 is a member selected from the group consisting of the following groupings: C7. g--, g --lower alkyl C-lower9. alkynyl 65 / N / N / N /N CH3 CE CEL3 A , ?--H,H -lowerH alkyl, C-lowerH alkynyl /. N. M. N. / N. . . . ; /...N. (=z p=2 =2 CE C3 C3 Ö-H, --OH, --O Acyl / N / N / N d=z (-o m (–Z 70 d-H, C-OE, C--O Acyl Z is a lower alkylene ketal, and Acyl is as defined above, / N / N / N with a strong acid selected from the group consisting of Z is selected from the group consisting of ketonic mineral and organic acids having a pK less than 1.5 in the oxygen and a lower alkylene ketal and Acyl is as presence of an alcohol of the formula ROH, in which R defined above • 75 has the meaning defined above. .. 8,231,56? 17 18 9. In a process for preparing ethers of estrone of the 15. A process for the preparation of compounds of the formula: formula:

CH CE O

O) 10 in which R is a hydrocarbon radical, X is a member Se RO lected from the group consisting of the following group ings: 15 C , C-H,H. Ö-lowerH. alkyl, C-lowerH. alkynyl where R is a hydrocarbon radical, the step which com / N / N / N / N prises reacting a member selected from the group con sisting of 5,6-epoxy-19-nor-androstane-3,17-dione 3,17 (H, CH3 CE: bis(ethylene ketal) 5,10-epoxy-19-nor-androstane-3,17-di 20 go do co one 3,17-bis(ethylene ketal) and mixtures of said 5,6 and C --H, 8-OH, C--O Acyl 5,10-epoxides, with a strong acid selected from the group consisting of mineral and organic acids having a pK less and Acyl represents the acyl radical of a hydrocarbon than 1.5 in the presence of an alcohol of the formula carboxylic acid containing from 1 to 4 carbon atoms ROH, where R has the meaning defined above, and recov 25 which comprises reacting a A5(6)-19-norsteroid of the ering the resulting ether of estrone. formula: 10. The process of claim 9 in which the alcohol is cyclopentanol and the resulting ether of estrone is estrone cyclopentyl ether. 11. In a process for preparing ethers of 17 oz-ethynyl 30 estradio of the formula:

H3C pH R--CCH in which X1 is selected from the group consisting of the following groupings: 7. pH OH. pH 40 C , C.--, d-lower alkyl, C-lower alkynyl RO / N / N / N / N (H. H. H. q=2 q=2 q=2 where R is a hydrocarbon radical, the step which com 45 C-H, C--OH, C-O Acyl prises reacting a member selected from the group con / N / N / N. sisting of 5,6-epoxy-17 oz-ethynyl-19-nor-androstane-173 Z is selected from the group consisting of ketonic oxygen ol-3-one 3-ethylene ketal, 5,10-epoxy-17 oz-ethynyl-19-nor and a lower alkylene ketal and Acyl is as defined above, androstane-17(3-ol-3-one 3-ethylene ketal and mixtures of in admixtures with the corresponding AC0 compound, said 5,6 and 5,10-epoxy compounds, with a strong acid 50 with a peracid to form the corresponding 5, 6 and 5, 10 selected from the group consisting of mineral and organic epoxy compounds and then treating the resulting mix acids having a pK less than 1.5 in the presence of an alco ture of epoxides with a strong acid selected from the hol of the formula ROH, where R is as defined above and group consisting of mineral and organic acids having a recovering the resulting ether of 17 oz-ethynyl estradiol. pK less than 1.5 in the presence of an alcohol of the for 12. The process of claim 15 in which the alcohol is mula ROH, in which R has the meaning defined above. cyclopentanol and the resulting ether of 17 oz-ethynyl 16. In a process for preparing estradiol, the step estradiol is the 3-cyclopentyl ether of 17 oz-ethynyl which comprises reacting a member selected from the estradiol. group consisting of 5,6-epoxy-19-nor-androstane-17f8-ol 13. A process for preparing estrone, which comprises 3-one 3-ethyleneketal, 5,10-epoxy-19-nor-androstane-17B reacting a mixture of A5(6) and A5(10) isomers of 19-nor 6) ol-3-one 3-ethyleneketal and mixtures of said 5,6- and androstene-3,17-dione 3,17-bis(ethylene ketal) with a per 5,10-epoxy compounds, with a strong acid selected from acid to form the corresponding 5,6 and 5,10-epoxy com the group consisting of mineral and organic acids hav pounds and then treating the resulting mixture of epox ing a pK less than 1.5 in solution in an inert, non-alco ides with a strong acid selected from the group consisting holic organic solvent, of mineral and organic acids having a pK less than 1.5 in 17. A compound of the formula: solution of an inert, non alcoholic solvent. 14. A process for preparing 3-hydroxy-176-acetyl-1,3, CH 5(10)-estratriene, which comprises reacting a mixture of /N A5(6) and A5C10) isomers of 19-nor-pregnene-3,20-dione 3, 20-bis(ethylene ketal) with a peracid to form the corre O sponding 5,6 and 5,10-epoxy compounds and then treat ing the resulting mixtures of epoxides with a strong acid selected from the group consisting of mineral and organic O acids having a pK less than 1.5 in solution of an inert, O > non alcoholic organic solvent. 75 - r. 3,231,567 in which x is selected from9 the group consisting of an- References Cited20 by the Examiner ethylenedioxy methylene group and a group: UNITED STATES PATENTS - CHs - 2,378,918 6/1945 Fernholz ------260-397.3 -o 5 2,729,654 1/1956 - Colton ------260-397.4 CK. OTHER REFERENCES Campbell et al., J.A.C.S., 80, pages 4717–21 (1958). 1 N Loewenthal, Tetrahedron, volume 6, No. 4, pages 269 o 303, pages 287-290 relied on. bias. - is er 19 O on androstane 3,17 -dione 3,17. l. 0 Tanabe et al., Chem. and Pharm. Bull, vol. 9, pp. 7-11 9. 56.10p-oxide-19-nor-androstane-3,17-dione 3,17- . (1961). bis20. (ethylene 5B,103-oxido-19-nor-pregnane ketal). - 3,20 - dione . 3,20-. . LEWIS GOTTS, Primary Examiner.0. bis (ethylene, ketal). - l6 HENRY A. FRENCH, Assistant Examiner.