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 steroids are already known in the literature and the prior verting steroids of the 19-nor-androstane 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 steroid 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 estrone 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.