US3231567A

US3231567A - Process for the preparation of 3-hydroxy- and 3-alkoxy-estratrienes and intermediates therefor

Info

Publication number: US3231567A
Application number: US330584A
Authority: US
Inventors: Ercoli Alberto; Gardi Rinaldo; Pedrali Cesare
Original assignee: Francesco Vismara SpA
Current assignee: Francesco Vismara SpA
Priority date: 1962-12-19
Filing date: 1963-12-16
Publication date: 1966-01-25
Anticipated expiration: 1983-01-25
Also published as: CH441304A; DK104301C; GB1055353A; BE641351A; DE1223379B

Description

United States Patent 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.

More particularly, 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:

and

in which R is a hydrocarbon radical and X is a member selected from the group consisting of the following groupings:

The term 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.

The term hydrocarbon radical used for R indicates.

a saturated or unsaturated, straight or branched, aliphatic moiety containing from 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. butyl, amyl, hexyl, heptyl, nonyl, decyl, dodecyl, miristyl, cetyl, stearyl, .allyl, crotyl 'propargyl, cytronellyl group; 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 1 to 8 carbon atoms, inclusive, cycloali-phatic moieties containing from 5 to 6 carbon atoms in the ring and the benzyl radical.

Methods for the aromatization of the ring A of l9-norsteroids are already known in the literature and the prior art teaches the conversion of a 3-keto-19-norsteroid of the androstane series into a derivative of the estrogenic series. This conversion may be accomplished by first preparing a 5,10-epoxy-estren-3-one or a 3-ketal thereof by epoxiding a 5(10)-estrene-3-one or A -3-keto-l9 -norsteroid 3-k'etal, respectively, with a peracid. The resulting 5,10-epoXy-estren-3-0ne or 3-ketal thereof is then converted to the same l0,8-hydroxy-4-estren-3-one by treatment with an alkali and the intermediate lOB-hydroxy compound is finally aromatized with acids to give a phenolsteroid (Journal Org. Chem, 23, 1744; 1958).

Thus, according to the piior art, 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.

We have now found that Sq-epoxy derivatives of 3-keto-l9-norstero ids and 3-ketals thereof can be directly converted, by one step only, to 3-hydroxy 1,3,5 (lO)-estra trienes when reacted with a strong acid in solution of an inert, non alcoholic organic solvent.

We have further found that 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.

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.

According to the present invention, opening of the oxido ring dehydration and rearrangement simultaneously occur by treatment of the fig-epoxy compounds with a strong mineral or organic acid in an appropriate organic solvent to give phenolsteroids or ethers, these latter if the organic solvent used in the reaction consists of or contains an alcohol reagent.

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:

wherein the epoxy group may have either the aor ,8- configuration, Z represents ketonic oxygen or a lower alkylene ketal and 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.

process of this invention and 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 phenolsteroidscan 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. a

For the preparation of phenolethers according to the invention, 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.

At the end of the reaction the desired estratriene separates. As said above, by operating in non alcoholic solvents there are obtained 3'-hydroxy-1,3, 5(l0)-estratrienes, while by operating in the presence of an alcohol or by using an alcohol as sole reaction solvent there are obtained 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.- Peracids 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.

If asstarting material for the epoxidation there is employed the total crude reaction product obtained by ketalization of a 19--nor-A -3-ketone, consisting of a mixture of 19-nor-A -3-keto 3-ethylene ketal and l9 -nor- A -3keto 3-ethylene ketal, there is produced upon epoxidation two isomeric epoxides that is 5, 6- and 5, 10-

I epoxides, which mixture can be directly employed for the of this invention are those having the formulas:

in which X represents a cycloethylenedioxy. methylene group or a' group -oxido-l9-nor-androstane-3,17-dione 3,17 bis(ethylene ketal) and 53,106,0xid0-19 nor pregnane-3,20-dione 3,20-- bis(ethylene ketal). Upon short heating with acids, 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.

invention. I Ihe'advantage in using the above'intermediates is given by the fact thatthe ketals of A and A -3-keto-19 norsteroids, from which the said 5,6 and 5,l-epoxides are produced, are now easily available by means of a new method recently developed and fully described in our US. copending applications Serial No. 228,242, filed on October 4, 1962, now patent No. 3,154,469, and Serial No. 279,304 filed on May 9, 1963. According to this method, the above ketals are produced by direct synthesis from the derivatives of the normal series through the corresponding 10,8-cyano-19-norsteroids.

The following examples are illustrative of the products and methods of this invention, but are not to be construed as limiting.

PREPARATION l.-l9 NOR (6)-ANDROSTENE- 3,17-DIONE 3,17-BIS(ETHYLENE KETAL) AND 19-(NOR-5(10)ANDROSTENE 3,17 DIONE 3,17- BIS(ETHYLENE KETAL) A solution of 2.4 g. of the 3B,17B-diacetoxy-5a-androstane-6-one (prepared by acetylation with acetic anhydride of the corresponding 35,17,8 dihydroxy compound) in 62 cc. of tetrahydrofuran and 6.2 cc. of water is treated under stirring with 600 mg. of sodium borohydride at room temperature for 4 hours. The excess of sodium borohydride is then decomposed by the addition of dilute acetic acid, the mixture poured into ice-water and the precipitate formed is collected by filtration, washed with water and dried under vacuum, thus giving 2 g. of 3,17- diacetate of 5a-androstahe-3fl,6,8,17fl-triol. The product recrystallized from dilute methanol melts at 130 131 'C.; [u] =-30i1 (chl. 0.5%).

To a solution of 1.2 g. of the diacetate of Soc-androstane-3fi,65,17,6-triol in 20 cc. of dry pyridine, cooled to 5 C., 1.6 cc. of notrosyl chloride is added dropwise with stirring. Stirring is continued for 4 hours and the temperature maintained at 5 C.; the mixture is then poured into ice-water to precipitate the Sa-ZIHdIOStaHe- 3,8,17 S-diacetoxy-6B-yl nitrite which is collected, washed with water and dried (yield 1.1 g.). After recrystallization from hexane-benzene the product melts at 152153 C. (dec.); [u] =55i1 (chl. 0.5%).

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. During the photolysis 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. after recrystallization from methyl alcohol; [oc] =-l66- 2 (chl. 0.5%). The compound dissolved in 40 cc. of ethanol is heated to reflux for 3 hours with 10 cc. of 2 N aqueous potassium hydroxide solution.

After cooling, the alcohol is removed and water is added to precipitate the 10-cyano-l9-hor 5-aridrostene- 3B,17B-diol which is collected, washed with water, dried and recrystallized from ethanol. M.P. 209-210" C., [a] =174 (dioxane).

A solution of 2.1 g. of lO-cyano-19-nor-5-androstene- 313,1713-diol in cc. of dry acetone is reacted under nitrogen atmosphere and at room temperature with 5 cc. of an 8 N solution of chromic acid (prepared by treating 26.7 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and by diluting the resulting mixture with distilled water to 100 cc.). The reaction mixture is stirred under nitrogen atmosphere for 5 minutes, then poured into ice-water saturated with sodium chloride and extracted with either. The ethereal solution is washed with water, dried over sodium sulfate and the ether evaporated to give 1.35 g. of IO-cyano-19-nor-5-androstene-3,17- dione, M.P. 152-156 C.; [a] =69 (chl. 0.5%).

To a solution of 840 mg. of the latter compound in 75 cc. of benzene is added 5 cc. of ethylene glycol containing 50 mg. of p-toluenesulfonic acid. The mixture is refluxed for 15 hours in the absence of moisture, then it is neutralized with a few drops of pyridine and concentrated under vacuum. The residue, recrystallized from methanol, gives 785 mg. of 10-cyano-19-nor-5-androstene-3,17-dione 3,l7-bis(ethylene ketal), M.P. 211212 C.; [a] =133 (chl. 0.5%).

850 mg. of the compound are dissolved in 350 cc. of boiling absolute ethanol and treated with 20 g. of sodium metal added little by little in the course of 2 hours. A portion of the alcohol is then distilled off and the remaining solution is cautiously diluted with water, while the temperature is maintained around 0 C. by cooling with ice. The mixture is extracted thoroughly with ether; the combined extracts are washed with water, dried and the solvent evaporated to give a mixture of 13 and A500) isomers of 19-nor-androstene-3,17-dione 3,17- bis(ethylene ketal).

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.). A second recrystallization from hexane affords the pure product, melting at 116117 C., [a] =-[-l0 (chloroform, c.=0.5%).

After evaporation of the methanolic mother liquor and recrystallization of the residue from methanol, there are obtained 0.1 g. of the tat-epoxy compound, 5a,10a-epoxy- 19-nor-androstane-3,17-dione 3,17-bis(ethylene ketal), melting at l20l21 C.; [a] =+2O (chloroform, c.=0.5%). After further elution of the column with benzene-ether (1:1) there is obtained the 5a,6a-oxido compound, 5a,6a-epoxy-19-nor-androstane 3,17 dione 3,17-bis(ethylene ketal) (yield 0.37 g.). The pure product melts at 191 C.; [a] =41 (chloroform, c.=0.5%).

Example 2 1 g. of SBJOfi-oxio-19-nor-androstane-3,17-dione 3,17- bis(ethylene ketal), obtained as described in Example 1,

. ing ethanol for fifty minutes.

is dissolved in cc. of acetone and heated to reflux for 2 hours with two drops of concentrated hydrochloric acid. The solution is evaporated under reduced pressure, the residue is diluted with water and the crystalline precipitate is filtered, washed with water and dried. There are obtained 0.580 g. of estrone melting at 253255 C. The melting point is undepressed with an authentic sample of estrone. 1

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. The residue is taken up with methanol and filtered. There are obtained 42 mg. of estrone cyclopentyl ether, melting at 152153 C.; [a] =-|-136 (dioxane, c.=0.5%).

By operating as described above but employing, as alcohol reagent, cyclohexanol, benzyl alcohol or cyclopentyl-propanol, instead of cyclopentyl alcohol, there are obtained estrone cyclohexyl ether, M.P. 156l57 C.; [a] =+134 (dioxane, c.=0.3%), estrone benzyl ether, M.P. 129130 C.; [a] =+132 (dioxane, c.=0.5%) and estrone cyclopentyl propyl ether, respectively.

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. 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), is dissolved without further. purification in 20 cc. of acetone and the solution heated to reflux for about 2 hours with 0.3 cc. of concentrated hydrochloric acid. 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.

Example 6 A solution of 1.2 g. of l9-nor-5(l0)-androstene-3,17- dione in 100 cc. of ether is treated at room temperature with 10 cc. of 15% ether solution of monoperphthalic acid to give 800 mg. of 5}3, 10fl-e-poxy-l9n=or-androstane 3,17-dione, melting at 143145 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

mixture heated to reflux for 1 hour. solution is concentrated under vacuum and the crystal- .line residue taken up with little aqueous acetone to 'give' 81 mg. of estrone melting at 256-258v C.

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.

Example 8 1 g. of the starting material of Example 5 is treated with 100 mg. of p-tol-uenesulfonic acid in cc. of boil- The alcohol is then removed under reduced pressure and the crude residue is diluted with water-to give a precipitate of estrone 3-ethyl ether melting at 126 C.; [a] =+150 (dioxane).

Example 9 100 mg. of 5,8,10pt-oxide-l9-nor-androstane-3,17-dione 3,17-bis(ethylene ketal) are dissolved inS cc. of cyclo- Example 1 2' g. of the mixture of 5,10- and 5,6-oxido compounds obtained in Preparation 1 is dissolved in cc. of acetonecontaining 8 g. of cetyl alcohol. The solution is refluxed for 2 hours with 1.5 cc. of perchloric acid to give estrone cetyl ether, melting at 6768 C.; [a] +95 (dioxane, c.=1%

- By substituting a corresponding amount of n-nonyl alcohol for cetyl alcohol, there is obtained estrone n-nonyl ether, M.P. 5658 'C.; [a] =+l14 C.=1% I, v

. Similarly, by reacting the starting material of this example with the appropriate alcohol in the presence of an' acid, such as those named above, there are produced other estrone ethers as, for example, the n. hexyl ether,

c.=l%), cinnamyl ether, M.P. 144145 C.

PREPARATION 2.19 NOR-5 (6) -PREGNENE-3 ,20- DIONE 3,20 -BIS(ETHYLENE KETAL) AND 19- NOR-5(10)-PREGNENE 3,20v DIONE 3,20 BIS ,(ETHYLENE KETAL) To a solution of 11.3 g. of the 3,20-diacetate of 5apregnane-BBQOfl-diol-done in cc. of tetrahydrofuran is added dropwise under stirring 45 cc. of an aqueous solution containing 1.1 g. of sodium borohydride. Stirring is continued for 8 hours at'room temperature and then the excess of sodium borohydride is decomposed by addition of dilute acetic acid. By pouring the mixture into ice-water a precipitate is formed which is filtered, washed with water and dried. There is thus obtained 8 g. of the diacetate of 5a-pregnane-3B,6B,20l3-triol. The product recrystallized from hexane shows melting point 169-171 C.; [a] =+3 (chloroform, c.=0.5%). The above compound (5.2 g.) is dissolved in 30 cc. of dry pyridine, cooled at 5 C. and treated little. by little with 2 cc. of nitrosyl chloride, with stirring 'while maintaining the temperature around 5 C. After afurther (dioxane,.

(dioxane,

9 4 hours at -5 C. the mixture is poured into ice-water until complete precipitation of the product which is filtered and dried thus giving 5.2 g. of 3B,20,8-diacetoxy-5etpregnane-6fl-yl nitrite. Recrystallization from methanolmethylene chloride yields the pure product melting at 153-154 C. (dec.); [a] =35 (chl. 0.5%).

A solution of 5 g. of the above compound in 100 cc. of anhydrous toluene is photolyzed in a Pyrex vessel at C. under pure nitrogen, using a Q81 watt high pressure mercury lamp with a Pyrex filter immersed into the reaction solution. After 3 hours, at the end of the irradiation, the precipitate formed is filtered, washed with toluene and dried, thus obtaining 1.45 g. of 313,205-diacetoxy- 19-nitroso-5a-pregnane-6B-ol (dimer) which recrystallized from acetone-hexane melts at 163-164 C.; [a] =4-3 (chl. 0.5%). By dilution of the mother liquor with petroleum ether there is obtained 1.2 g. of 35,20,9-diacetoxy-19-oximino-Sa-pregnane-GB-OI.

Total yield: 2.65 g. equal to 53%. The pure 19-oxim- -ino compound, recrystallized from ethyl acetate, shows melting point 218-219 C.; [a] =-25 (chl. 0.5%).

A mixture of the 19-oximino compound and the nitroso-dimer (2 g.), as obtained above, is dissolved in 37 cc. of dry pyridine and treated with 6 cc. of phosphorus oxychloride. The mixture is kept at room temperature under anhydrous conditions for hours, after which the product is precipitated by the addition of ice-water and collected. There is thus obtained 1.6 g. of 10-cyano-l9- nor-5-pre gnene-3;8,20/3-dio1 diacetate.

After recrystallization from methanol-methylene chloride the. melting point is 189190 C.; [a] =127i1 (chl. 0.5%

A solution of 1 g. of this compound in 40 cc. of methanol is treated to reflux for 2 hours with 10 cc. of aqueous sodium hydroxide solution. By cooling and diluting with water there is obtained 700 mg. of IO-cyano- 19-nor-pregnene-3;8,20B-diol melting at 272-273 C., after a recrystallization from methanol; [a] =-18O (chl. 0.5

The compound dissolved in dry acetone is treated under nitrogen atmosphere with 1 cc. of 8 N solution of chromic acid to give 10-cyano-19-nor-5-pregnene-3,ZO-dione, MP. 188-192 C.

4 g. of this compound is added to a solution of 300 cc. of anhydrous benzene containing cc. of ethylene glycol and 250 mg. of p-toluenesulfonic acid and the mixture refluxed for 15 hours. After neutralization with a few drops of pyridine, the liquid is evaporated under vacuum and the residue recrystallized from methanolmethylene chloride to give 10-cyano-19-nor-5-pregnene- 3,20-dione 3,20 bis(ethylene ketal).

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).

The crude product is dissolved in 15 cc. of acetone and heated to reflux for 2 hours with 0.5 cc. of dilute hydrochloric acid. The solution is then evaporated under re duced pressure and the residue diluted with Water to give 0.6 g. of 3-hydroxy-17fi-acetyl-1,3,5(10)-estratriene, melting at 247-249 C.; [oc] =+159 (chloroform, 0.: 0.5

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. The reaction mixture is heated to reflux for fifty minutes, then diluted with water and the product which precipitates filtered and recrystallized from methanol to give 3-methoxy-17p-acetyl-1,3,5(10)-estratriene, melting at 134-136 C.; [a] =+160 (chloroform, c.=0.5%).

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. of n-hexyl alcohol and the solution heated for 2 hours on boiling water bath with 2 drops of concentrated hydrochloric acid to give estradiol n-hexyl ether, melting at 70-71 C.; [a] =+65 (dioxan'e,

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.

1 g. of this product is treated with 20 cc. of 2-methyl- 2-ethyl dioxolane and 30 mg. of p-toluenesulfonic acid. The reaction mixture is'heated for about hours, then it is neutralized with sodium carbonate and the benzene is completely evaporated under vacuum. The residue, taken up with dilute methanoL'gives 3-ethylenedioxy-10- cyano-19-nor-5-androstene-17-one. 2 g. of the 3-monoketal, dissolved in 40 cc. of anhydrous toluene are treated with potassium t. vamylate. 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.

Then 1.2 g. of lithium in small pieces are introduced over a period of 90 minutes and the mixture is maintained under stirring until the blue color. of the solution 1.5 g. of the total crude product obtained in Preparation 3 is dissolved in 150 cc. of ether and treated with 10 cc. of a 20% ethereal solution of perbenzoic acid.

The mixture is allowed to stand overnight at room temperature, then washed with a 5% solution of sodium bicarbonate, a saturated solution of sodium chloride and finally with water until neutrality. The dried solution is evaporated under reduced pressure and the residue is taken up with a mixture of methylene chloride-methanol to obtain a mixture of 5,6- and 5,10-epoxides of 17aethynyl-l9-noraandrostane-17/3-ol-3-one 3-ethylene ketal more precisely 50,6a and SAIOB-oxides.

The mixture of isomeric epoxides is dissolved in .50 cc. of benzene and 10 cc. of cyclop entanol and heated to reflux with 80 mg. of benzenesulfonic acid. After cooling, the reaction mixture is diluted with water and the precipitate thus obtained is collected by filtration, to give the 3 -cyclopentyl ether of the 17er-ethynyl-estradiol, melting at 107-108 C.; [u] =+5 (dioxane, c.=0.5%).

Similarly, by reaction with the appropriate alcohol reagent, there are produced other 3-et hers of 17u-ethynyl estradiol, such as for example the ethyl, propyl, isopr-opyl, n-butyl, n-amyl, cyclohexyl and benzyl ethers.

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. The solution is then evaporated under reduced pressure and the residue diluted with water to give 17a-acetoxy-17fl-acetyl-1,3,5 (10)-estratriene-3-ol, melting at 242244 C.; [cc] =+49 (chloroform, c.=0.5%

' 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).

The crude product is dissolved in 15 cc. of acetone and heated to reflux for 2 hours with 0.5 cc. of sulfuric acid. The solution is then evaporated under reduced pressure and the residue diluted with water to give 17,8-acetyl- 1,3,5'(10)-SI'Etil'i611-3,17u-Cli0l, melting at 240242 C.; [a] =+9O.5 (dioxane). V i V W Example 21 The 5,10-oxido compound obtained in admixture with the corresponding 5,6-oxido derivative, according to the procedure of Example 20, is purified by recrystallization from methanol to give 5B,lofi epoxy-19-nor-pregnane-17aand recrystallized from methanol to give 3-methoxy:17flacetyl-1,3,5(10)-estratriene-17a-ol, melting at ISO-152 C.; [a] =+45.=5 (dioxane, c.=0.5%

We claim: i 1. In a process for'the of the formula:

preparation of phenolsteroids wherein X is a member selected from the group consitsing of the following groupings:

0 0H 0H OH and 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:

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;

(b) a 5,10-epoxide of the formula:

in which X and Z are as defined above; and (c) a mixture of said corresponding 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 solution of an inert, non alcoholic organic solvent.

2. In a process for the preparation of phenolsteroids of the formula:

OHa

wherein X is a member selected from the group consisting of the following groupings:

and Acyl represents the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 4 carbon atoms, the

14 step which comprises reacting a fl,'y-epoXy-3-keto-l9-r1orsteroid derivative of the formula:

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.

3. In a process for the preparation of phenolsteroids of the formula:

in which 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:

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.

4. A process as defined in claim 1 in which the strong acid is hydrochloric acid and the non alcoholic organic I 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-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

6. In a process for preparing 17u-ethynyl estradiol the step 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.

7. In a process for the preparation of phenolethers of the formula:

CH3 it] wherein R is a hydrocarbon radical, X is a member selected from the group consisting of the following groupmgs:

and 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:

in which R is a hydrocarbon radical, X is a member selected from the group consisting of the following groupings:

and 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

in which 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. 1

9. In a process for preparing ethers of estrone of the formula:

where 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.

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 17ot-ethynyl estradiol of the formula:

H30 OH i -"CECH where R is a hydrocarbon radical, the step which comprises reacting a member selected from the group consisting of 5,6-epoxy-17a-ethynyl-l9-nor-androstane-l7flol-3-one 3-ethylene ketal, 5,l-epoxy-l7a-ethynyl-l9norandrostane-l7f3-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 the presence of an alcohol of the formula ROH, where R is as defined above and recovering the resulting ether of 17OL-6thYl1Yl estradiol.

12. The process of claim 11 in which the alcohol is cyclopentanol and the resulting ether of l7rx-ethynyl estradiol is the 3-cyclopentyl ether of 17a-ethynyl estradiol.

13. 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.

14. 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.

15. A process for the preparation of compoundsof the formula:

in which R is a hydrocarbon radical, X is a member .se-

.lected from the; group consisting of the following group- X1 P l in which X is selected from the group consisting of the following groupings:

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.

16. 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.

17. A compound of the formula:

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).

20. 5p,10;3-oxido-19-nor-pregnane 3,20 dione 3,20- 1 LEWIS GOTTS Pr'mary Exammer bis (ethylene ketal). v v Y 15 HENRY A. FRENCH, Assistant Examiner.

Tanabe et al., Chem. and Pharm. Bull, vol. 9, pp. 7-11

Claims

1. IN A PROCESS FOR THE PREPARATION OF PHENOLSTEROIDS OF THE FORMULA