Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J75/00—Processes for the preparation of steroids in general

Definitions

• This invention relates to an improved process for converting steroids of the 19-nor-androstane and 19-n0r-pregnane series into derivatives of the estrogenic series.
• the invention also relates to certain new 19-norsteroid derivatives useful as intermediates in said conversion.
• this invention is concerned with a method for the aromatization of the ring A to produce 3-hydroxy-1,3,5(lO)-estratrienes and ethers thereof represented by the following formulas:
• R is a hydrocarbon radical and X is a member selected from the group consisting of the following groupings:
• lower alkyl is represented by methyl, ethyl, propyl and butyl radicals; the term lower alkynyl includes ethynyl, propynyl and butynyl, and Acyl represents the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 4 carbon atoms, the acetyl radical being preferred.
• hydrocarbon radical used for R indicates.
• a hydroxy substituted lower alkylene group such as hyice droxy ethylene, hydroxy propylene, hydroxy butylene and the like
• a saturated or unsaturated cycloaliphatic moiety such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclopentylpropyl, cycloheptyl, cyclooctyl radical; or an araliphatic moiety, such as benzyl, phenetyl, cynnamyl radical.
• Preferred hydrocarbon radicals are aliphatic moieties containing from
• the aromatization of the ring A is accomplished by a two step process through the intermediate 1Ofl-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 a hydrocarbon halide.
• ethers of 3-hydroxy-1,3, 5(10)-estratrienes can be also obtained from .Byy-epoxy derivatives of 3-keto-19-norsteroids and 3-ketals thereof by one step only, when the treatment of said epoxy-l9- nor-compoun'ds with a strong acid is carried out in the presence of an alcohol.
• the ⁇ Ly-epoxy compounds which directly aromatize to give phenolsteroids or ethers according to the procedures of the present invention are 5,6-epoxy 3-keto-l9-norsteroids, 5,10-epoxy 3-keto-19-norsteroids and 3-ketals of said 5,6 and 5,10-epoxy 3-keto compounds.
• the 5,6 or 5,10-epoxy compounds may be employed either in a or in fl-form.
• a 50,6aor a 55,6;8-epoxy derivative instead of employing a 50,6aor a 55,6;8-epoxy derivative alone, one may employ mixtures of said isomers or also mixtures of the corresponding 5,6- and 5,10-epoXy derivatives, that is a 5,6-epoxy 3-keto-l9-norsteroid together with the corresponding 5,10-epoXy compound-or a 5,6-epoxy 3-ke'to-l9-norsteroid 3-ketal in admixture with the 3-ketal of the corresponding 5,10-epoxy derivative.
• the invention thus provides a general method for the aromatization of the ring A of the steroid nucleus through firy-epoxy-3-keto-19-norsteroids.
• the invention also provides new and useful intermediates in said method for the preparation of phenolsteroids, particularly of estrone and its ethers and of 3- hydroxy-17/8-acetyl-1,3,5(10)-estratriene and its ethers.
• the ,8,'y-epoxy-3-keto compounds used for the process of this invention may-be represented by the following general formulas:
• epoxy group may have either the aor ,8- configuration
• Z represents ketonic oxygen or a lower alkylene ketal
• X represents a member selected from the group consisting of the following groupings:
• 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 butylene glycol, 1, S-butylene glycol and the like.
• ferredvketal group is ethylene glycolketal.
• the strong acids 'whichcan be employed in the process of this invention are mineral acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, pyrophosphoric acid, iodic acid; acids such as dichloroacetic acid, trichloroacetic acid, oxalic acid, arylsulfonic acids and the like. Acids which or strong organic have a pK less than 1.5 are considered strong acids for the.
• any of these may be employed 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 aromatization, but a molecular amount or an excess may be used without'damag e.
• the organic, non alcoholic solvents which are employed for the aromatization step in order to obtain phenolsteroids can be selected from benzene, toluene, hexane, cyclohexane and other hydrocarbons, acetone, dioxane, tetra-v hydrofuran or halogenated" organic solvents, such as methylene chloride, chlorobenzene, chloroform and carbon tetrachloride; preferred non alcoholic solventis acetone.
• the reaction is carried out in the presence of an alcohol of the formula ROI-I, in which R has the meaning defined above, or by using an alcohol of the formula ROH as sole reaction solvent.
• Thev aromatization step can be performed at tempera tures between the room temperature and the boiling pointv 45 Prer of the solvent or of the solvent mixture employed; pref-- erably the reaction is carried out by heating to reflux the reaction mixture for a period of time varying from about ten minutes to about four hours.
• estratriene separates.
• non alcoholic solvents there are obtained 3'-hydroxy-1,3, 5(l0)-estratrienes
• ethers of 3-hydroxy-1,3,5(l0)-estratrienes in which the etherifying groupcorresponds to the hydro carbon moiety of the alcohol employed.
• the ,8,' -epoxy-3-keto compounds of the general Formulas III and IV, used as intermediates in the process of this invention, areobtained by treating the corresponding 19--- nor-eompounds, N or M -unsaturated, with a peracid, under the usual conditions for epoxide formation.
• a peracid employed are: performic acid, peracetic acid,. perbenzoic acid, monoperphthalic acid or hydrogen peroxide.
• the epoxy compounds obtained at the end of the reaction consists in general of a mixture of 0c and B epimers which can be separated according to known methods, i.e., by chromatography.
• I epoxides which mixture can be directly employed for the of this invention are those having the formulas:
• X represents a cycloethylenedioxy.
• the: above intermediate epoxides aroinatize in very good yield, with simultaneous hydrolysis of the ketal grou s at the: 17- or 20-position, 'to give the corresponding phenolv steroids or phenolethers according to the process of this.
• a solution of 5.8 g. of the nitrite in 100 cc. of dry toluene in a Pyrex vessel is irradiated by means of a 200- watt mercury arc lamp for 3 hours at a temperature of about C., while a stream of dry nitrogen free from oxygen is passed into the vessel.
• the solution becomes turbid because the oximino derivative, which formed, separates.
• the solid material is then filtered, washed with toluene, dried and recrystallized from benzene to give 3.2 g. of the nitroso-dimer corresponding to the 19-oximino-5a-androstane313,6;3,17/3- triol-3,l7-diacetate melting at 162163 C.;
• a solution of 1.7 g. of the nitroso-dimer is 50 cc. of dry pyridine is treated, at a temperature around 0 C., by dropwise addition with 10 cc. of phosphorus oxychloride.
• the reaction mixture is stirred at room temperature under anhydrous conditions for 20 hours, then poured into ice-water and extracted with either.
• the ethereal solution is washed with dilute hydrochloric acid and an aqueous solution of sodium bicarbonate, successively, then with water and, after being dried over magnesium sulphate, is concentrated to obtain 1.3 g. of 10-cyano-19- nor-5-androstene-3B,l7/3-diol, diacetate.
• the product melts at 160-161 C.
• Example 1 2 g. of the total residue obtained in Preparation 1, consisting of a mixture of 19-nor-5(6)-androstene-3,l7- dione 3,17-bis(ethylene ketal) and 19-nor-5(10 )-androstene 3,17 bis(ethylene ketal), is dissolved in 200 cc. of ether and treated at 5 C. with 20 cc. of a 15% ether solution of monoperphthalic acid. After standing overnight at room temperature, the etheral solution is washed with a 5% sodium carbonate solution, a saturated aqueous solution of sodium chloride and water, then dried and concentrated under vacuum to dryness.
• the residue (about 2 g.) consists of a mixture of 5,6- and 5,10-oxides of 19-nor-and1 ostane-3,17-dione 3,17-bis- (ethylene ketal).
• the mixture of 5,6- and 5,10-oxides thus produced may be used without further purification for the aromatization step. It is possible however to separate the isomeric epoxides by chromatography over activated magnesium silicate (Florisil). Elution with benzene-ether (3:2) gives the 5,10-oxide.
• Recrystallization of the 5,10-oxido compound from methanol provides the fi-epoxy compound, 5,8,10/3-epoxy- 19-nor-androstane-3,17-dione 3, 17-bis (ethylene ketal) (yield 1.35 g.).
• Example 2 1 g. of SBJOfi-oxio-19-nor-androstane-3,17-dione 3,17- bis(ethylene ketal), obtained as described in Example 1,
• estrone melting is obtained at 253255 C. The melting point is undepressed with an authentic sample of estrone.
• Example 3 100 mg. of 5oz,10a-oxido-19-nor-androstane-3,17-dione 3,17-bis(ethylene ketal), obtained as described in Example. 1, is heated to reflux for 1 hour in an acetone solution containing two drops of 40% sulfuric acid to give estrone, M.P. 254-255 C. The melting point is undepressed with an authentic sample of estrone.
• Example 4 pentanol and treated with 2 drops of concentrated hydrochloric acid.
• the reaction mixture is heated for-1 hour on boiling Water bath and the alcohol in excess is evaporated under reduced pressure.
• -136 (dioxane, c. 0.5%).
• Example 10 100 mg. of 5,8,10,8oxido-l9 n or-androstane l7u methyl- 17/3-ol-3-one 3-ethylene ketal (prepared as described in J.A.C.S., 81, 3120; 1959) is dissolved in cc. of hexane and treated on boiling water bath with 0.5 cc. of trichloroacetic acid. Afterevaporation of the solvent and dilution with Water. there is obtained 55 mg. of 17amethyl estradiol, melting at 185-187 C.
• Example 9 Theprocedure of Example 9 is applied to the starting material of this example to produce 3-cyclopentyl ether of 17a-methyl
• the mixture of 5,6 and 5,10-oxides obtained as total residue in Example 1 (about 2 g.) containing 5,6-epoxyl9-nor-androstane-3,17-dione 3,17-bis(ethylene ketal) and 5,10-epoxy-19-nor-androstane-3,17-dione 3,17 bis (ethyl-. ene ketal)
• the mixture is then cooled and diluted with Water and the product which precipitates .is recovered by filtra tion. By recrystallization from acetone there is obtain d. pure estrone, melting at 8260 C.
• the 5,10-oxido compound (100 mg), dissolved in 5 cc. of acetone is treated with two drops of concentrated hydrochloric acid and the After cooling, the
• Example 7 1 g. of 5B,10,8-oxido-19-nor-androstane-17B-ol-3-one (prepared as described in J. Org. Chem., 23, 1744; 1958) is treated according to the procedure of Example 2 with hydrochloric acid in acetone solution to give 700 mg. of estradiol',M.P. 173-175" C.
• estrone ethers as, for example, the n. hexyl ether
• This compound is treated with sodium metal in absolute ethanol in the same manner as shown in Preparation 1 for the corresponding 10-cyano-19-nor-5-androstene-3,17-dione 3,17-bis(ethylene ketal).
• the product of the reaction consists of l9-nor-5(10)-pregnene-3,20 dione 3,20-bis (ethylene ketal) in admixture with little 19- non-5(6)-pregnene-3,20-dione 3,20-ois(ethylene ketal), melting at 134-140 C.
• Example 12 2 g. of the product obtained in Preparation 2 are dissolved in 200 cc. of ether and treated at 5 C. with 60 cc. of a 15% ethereal solution of monoperphthalic acid. The reaction mixtu-re is allowed to stand overnight at room temperature, then washed with a 5% aqueous solution of sodium bicarbonate, a saturated sodium chloride solution and with Water until neutrality and finally dried and evaporated under reduced pressure to dryness.
• the crude residue consists of 5,lO-epoxy-19-nor-pregnane-3,20-dione 3,20-bis (ethylene ketal) in admixtures with traces of 5,6- epoxy 19 nor-pregnane-3,20-dione 3,20-bis(ethylene ketal).
• Example 13 The 5,10-oxido compound obtained in admixture with the corresponding 5,6-oxido compound according to the procedure of Example 12 is purified by chromatography over activated magnesium silicate. Elution with benzeneether (3:2) provides the pure 5,8,10,8-oxido compound, 5,8, l OB-epoxy-l 9-nor-pregnane-3 ,20-dione 3 ,20-bis (ethylene ketal), melting at 136-137 C.; [a] +58 (chloroform). 1.5 g. of this compound is treated with 50 cc. of methanol and 100 mg. of p-toluenesulfonic acid.
• Example 14 1 g. of l9-nor-testosterone B-e'thylene ketal is dissolved in cc. of ether and treated at room temperature with 5 cc. of a 20% ethereal solution of monoperphthalic acid to give a mixture of 5,6 and5,10-oxido compounds which can be separated according to the procedure described in J.A.C.S., 81, 3120; 1959.
• the total crude product is treated with 0.8 cc. of dichloroacetic acid in 15 cc. of hexane solution, under the conditions described in the preceding examples, and converted to estradiol.
• Example 15 1 g. of 55,10B-oxido-l9-nor-pregnane-3,20-dione 3,20- bis (ethylene ketal) are dissolved in 15 cc. of cyclopentanol and treated with 0.5 cc. of concentrated hydrochloric acid. The reaction mixture is heated for 1 hour on boiling water bath and the alcohol in excess is evaporated under reduced pressure. The residue is taken up with methanol and filtered. There is obtained 0.8 g. of 3-cyclopentyloxy-17/3-acetyl-1,3 ,5 10) -estratriene, melting at 112-114 C.; [a] -+138 (dioxane).
• Example 16 mg. of 19- nor-testo'sterone 3-propylen'e ketal (obtained by treating 19-nor-testosterone with 1,2- propylene glycol in the presence of p-toluenesulfo'nic acid) are dissolved in 5 cc. of ether and treated at 5 C. with 5 cc. of a 15% ethereal solution of perace'tic acid to obtain a mixture of 5,6- and 5,10-oxides of 19-norandrostane-l7fi-ol-3-one 3-propylene ketal. The total crude produ-ct is dissolved, without further purification, in 5 cc.
• PREPARATION 3 2 g. of 10-cyano-l9-nor-5-androstene-3/3,17fi-diol, obtained as described in Preparation 1, is treated with 2.5 g. of aluminum ispopropoxide and 25 cc. of cyclohexanone in anhydrous toluene solution. The mixture is heated to reflux for 3 hours, distilling, from time to time, little quantities of the solvent. After adding water acidulated with hydrochloric acid, the toluic layer is separated and the mother-liquors are extracted with ether. The organic layers are collected, washed, dried and evaporated. From the residue extracted again with ether, 1.350 g. of IO-cyano-19-nor-A -and-rostene-3,l7- dione is obtained, which after recrystallization from methanol melts at 183-185 C.
• a slow stream of purified acetylene is bubbled in the solution-for 20 hours at room temperature after which thereaction mixture is poured into a mixture of ice-water containing hydrochloric acid. The organic layer is separated and the liquor evaporated 'to give -cy-ano-17a-ethynyl-19-nor-5-androstene-17,8-01- 3-one 3-ethylene' ketal.
• a solution of 10-cyano-3- monoketal in 60 cc. of dry ether and 60 cc. of dry dioxane is dropped into 400 cc. of liquid ammonia.
• Example 18 17 m-ethyl-19-nor-testosterone 3-ethylene ketal is treated with .perbenzoic; acid according to the procedure of Example 17 to produce a mixture of isomeric epoxides (5,6 and 5,10-oxides) of Ila-ethyl-19-nor-androstane- 17B-ol-3-one 3-ethylene ketal.
• the mixture of the 5,6 and 5,10-oxides thus produced is treated with cyclopentyl alcohol and benzenesulfonic acid as in the same Example 17 to obtain 3-cyclopentyl ether of 17oethylestradiol,
• Example 19 850 mg. of 17a-acetoxy-19-nor-progesterone-3-ethylene ketal (obtained by treating 17a-acetoxy-19-nor-progesterone with ethylene glycol in the presence of p-toluenesulfonic acid under mild conditions) are dissolved in 80 cc. of ether and treated at.5 C. with 5 cc. of a ethereal solution of monoperphthalic acid. The mixture 12 is allowed to stand overnight at room temperature, then washed with a 5% aqueous solution of sodium bicarbonate, a saturated sodium chloride solution and with Water until neutrality and finally dried and evaporated under reduced pressure to dryness.
• the crude residue consists of 5,10-epoxy-17a-acetoxy-19-nor-preguane-3,20- dione 3-ethylene ketal in admixture with traces of 5,6- epoxy-17a-acetoxy-19 -nor-pregnane-3,20-dione 3-ethylene ketal.
• the crude product is dissolved in 15 cc. of acetone and heated to reflux for 2 hours with 0.5 cc. of concentrated hydrochloric acid.
• Example 20 l g. of l7ot-hydroxy-19-nor-progesterone 3,20-bis(et-hylene ketal) (obtained by heating 17u-hydroxy -19-norprogesterone for 15 hours at reflux with ethylene glycol in the presence of benzenesulfonic acid), is dissolved in 50 cc. ofether'and treated at 5 C. with 15 cc. of a 15% ethereal solution. of perbenzoic acid. The reaction mixture is allowed to stand overnight at room temperature, then washed-with a 5% aqueous solution of sodium bicarbonate, a saturated sodium chloride solution and with Water until neutrality, then dried and evaporated under vacuum to dryness.
• the crude residue consists of 5,10- epoxy 19-nor-pregnane-17a-ol-3,20-dione 3,20-bis(ethylene ketal) in admixture with traces of 5,6-epoxy-l9-norpreguane-17uol-3,20-dione 3,20-bis (ethylene ketal).
• Acyl represents the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 4 carbon atoms, the step which comprises reacting a fi,'y-epoxy3-keto-19-nor steroid derivative selected from the group consisting of (a) a 5,6-epoxide or" the formula:
• X is a member selected from the group consisting of the following groupings:
• Z is selected from the group consisting of ketonic oxygen and a lower alkylene ketal and Acyl is as defined above;
• X is a member selected from the group consisting of the following groupings:
• Acyl represents the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 4 carbon atoms
• X is a member selected from the group consisting of the following groupings:
• Z is selected from the group consiting of ketonic oxygen and a lower alkylene ketal and Acyl is as defined above, 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.
• X is a member selected from the group consisting and Acyl represents the acyl radical of a hydrocarbon carbo'xylic acid containing from 1 to 4 carbon atoms
• the step which comprises reacting a 5,10-epoxy-3-keto- 19-norsteroid derivative of the formula:
• X is a member selected from the group consisting of the following groupings:
• Z is selected from the group consisting of ketonic oxygen and a lower alkylene ketal, and Acyl is as defined above, 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.
• estrone in a process for preparing estrone the step which comprises reacting a member selected from the group consisting of 5,6--epoxy-l9-nor-androstane-3,l7-dione 3,17- bis(ethylene ketal), 5,10 epoxy 19-nor-androstane-3,17- 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 a pK less than 1.5 in solution of an inert, non alcoholic organic solvent. 1
• a process for preparing 17u-ethynyl estradiol which comprises reacting a member selected from the group consisting of 5,6-epoxy-17a-ethynyl-19-nor-androstane-17fi-ol-3-one 3-ethylene ketal, 5,10-epoxy-l7a-ethynyl-tl9-nor andarostane-l7,8-ol-3-one 3-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 a pK less than 1.5 in solution of an inert,'non alcoholic organic solvent.
• R is a hydrocarbon radical
• X is a member selected from the group consisting of the following groupmgs:
• Acyl represents the acyl radical of a hydrocarbon in which X is a member selected from the group consisting of the following groupings:
• Z is selected from the group consisting of ketonic oxygen and a lower alkylene ketal and Acyl is as defined above 16 (b) a 5,10-epoxide of the formula:
• R is a hydrocarbon radical
• X is a member selected from the group consisting of the following groupings:
• Acyl represents the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 4 carbon atoms, the step which comprises reacting a 5,10-epoxy-3-keto-l9-norsteroid derivative of the formula: 1
• X is a member selected from the group consist- Z is a lower alkylene ketal, and Acyl is as defined above, with a strong acid selected from the group consisting of mineral and organic acids having a pK less than 1.5 in the .presence of an alcohol of thezformula ROH, in which R has the meaning defined above.
• R is a hydrocarbon radical
• the step which comprises reacting a member selected from the group consisting of 5,6-epoxy-l9-nor-androstane-3,17-dione 3,17- bis(ethylene ketal) 5,10-epoxy-19-nor-androstane-3,l7-dione 3,17-bis (ethylene ketal) and mixtures of said 5,6 and 5,10-epoxides, with a strong acid selected from the group consisting of mineral and organic acids having a pK less than 1.5 in the presence of an alcohol of the formula ROH, where R has the meaning defined above, and recovering the resulting ether of estrone.
• a process for preparing estrone which comprises reacting a mixture of A and A isomers of l9-norandrostene-3,l7-dione 3,l7-bis(ethylene ketal) with a peracid to form the corresponding 5,6 and 5,10-epoxy compounds and then treating the resulting mixture of epoxides 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 solvent.
• a process for preparing 3-hydroXy-l7fl-acetyl-1,3, (10)-estratriene which comprises reacting a mixture of 13 and A isomers of 19-nor-pregnene-3,20-dione 3, 20-bis(ethylene ketal) with a peracid to form the corresponding 5,6 and 5,10-epoxy compounds and then treating the resulting mixtures of epoxides 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.
• R is a hydrocarbon radical
• X is a member .se-
• OH OH Z is selected from the group consisting of ketonic oxygen and a lower alkylene ketal and Acyl is as defined above, in admixtures with the corresponding A500) compound, with a peracid to form the corresponding 5, 6 and 5, 10- epoxy compounds and then treating the resulting mixture of epoxides with a strong acid selected from the group consisting of mineral and organic acids having a pK less than 1.5 in the presence of an alcohol of the formula ROH, in which R has the meaning defined above.
• estradiol In a process for preparing estradiol, the step which comprises reacting a member selected from the group consisting of 5,6-epoxy-19-nor-androstane-1713-01- 3-one 3-ethyleneketal, 5,lO-epoxy-19-nor-androstane-l76- ol-3-one 3-ethyleneketal 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 a pK less than 1.5 in solution in an inert, non-alcoholic organic solvent.
• a strong acid selected from the group consisting of mineral and organic acids having a pK less than 1.5 in solution in an inert, non-alcoholic organic solvent.
• bis (ethylene ketal) in whieh X is selected from the 'gfefi p cohsistihg of an Referenes 'Cited by the Examiner ethylenedioxy methylene group and a group: UNITED STATES PATENTS R 2,378,918 6/1945 Fernholz 260-3973 I 5 7 2,729,654 1/1956 7 Colton 260--397.4 c r OTHER REFERENCES Campbell et a1., I.A.C.S., 80, pages 4717-21 (1958 Loewenthal, Tetrahedron, volume 6, No. 4, pages 269- 18. 5a,10nt-oxide-19-nor-androst;ape-3,17-dipne 3,17- 10 Pages 287-290 relied bis (ethylene ketal).

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