3,340,279 United States Patent Office Patented Sept. 5, 1967 2 3,340,279 3-enol-ether group, the 3-keto group must be temporarily 7-METHYL-STERODS OF THE OESTRANE protected, for instance by ketalization in a conventional - SERIES manner, such as by reaction of the A5(10)-3-keto-steroid Hendrik Paul de Jongh and Nicolaas Pieter van Vliet, Oss, with an aliphatic alcohol and a weak acid. Another possi. Netheriands, assignors to Organon Inc., West Orange, bility is to prepare the 3-thioketal by reaction of the N.J., a corporation of New Jersey 3-enol-ether compound with an alcohol. No Drawing. Filed June 1, 1965, Ser. No. 460,476 The starting products may already have a lower alkyl or Claims priority, application Netherlands, June 16, 1964, alkenyl group in 17-position, but it is also possible to 64-6,797 introduce these groups at a later stage. 3 Claims. (C. 260-397.4) 0. The 3-ether group is usually a lower aliphatic hydro carbon radical, preferably a methyl group. The reduction of the aromatic compound to the corre ABSTRACT OF THE DISCLOSURE sponding A2,5(10)-3-alkoxy compound is performed by 7c-methyl-steroids of the oestrane series, which contain treating the former steroid with an alkali metal in liquid a keto group at the 3-position, and which may be substi 5 ammonia and an alcohol. For preference lithium is used. tuted at the 17-position by lower alkyl, alkenyl or alkynyl, The thus obtained A2,5(10)-3-alkoxy-oestradiene com and their esters of inorganic acids and of organic acids pound is next converted into the corresponding A5(10)-3- containing from 1 to 18 carbon atoms, such as, for exam keto-compound by treatment with an acid under mild con ple, A5(0) - 3 -keto-7c-methyl-176-hydroxy-17a-ethinyles ditions. trene, are valuable hormones possessing both androgenic 20 For this hydrolysis oxalic acid is usually applied together and anabolic activity. with an aqueous alcohol, for instance methanol, for 20-60 minutes, but other weak organic acids, too, such as acetic acid, propionic acid or butyric acid, can be used. As in The invention relates to novel 7a-methyl-steroids of the the reduction of the aromatic ring A a possibly present oestrane series and to a process for the preparation thereof. 25 17-keto, or 17-alkynyl group is reduced simultaneously, More particularly, it relates to the preparation of a new and a 17-ester group is split off reductively, the starting group of compounds having the formula: product is preferably a 17.5-hydroxy-steroid, or a 17(3- hydroxy-17-alkyl, or 17-alkenyl-steroid. After reduction, or possibly, at a later stage, after hy 30 drolysis of the 3-enol-ether group, the 17,3-hydroxy group can be esterified, and/or a 17-alkynyl group introduced by oxidation of the 176-hydroxy compound, followed by an alkynylation reaction, if desired, followed by esterifica tion of the obtained 17(3-hydroxy-17a-alkynyl compound. o 35 Instead of starting from a 17c-alkyl, or 17 oz-alkenyl compound it is naturally also possible to introduce these R=a keto group, or the group OX (c.Y), in which X is groups at a later stage. Then a 17B-hydroxy-steroid is hydrogen, or an acyl group, and Y is hydrogen or a taken as starting material, after which the A2,5(10)-3- lower alkyl, alkenyl, or alkynyl group. alkoxy-7 oz-methyl-176-hydroxy-steroid obtained as inter These compounds are prepared by starting from a com 40 mediate product, or the A5(0)-3-keto-70-methyl-176-hy pound of the formula: droxy compound obtained after hydrolysis of this com pound, is oxidized and next submitted in the usual manner O R to a 17-alkylation reaction, if desired, followed by esterifi cation of the thus obtained 17-hydroxy-17a-alkyl com H as R. 45 pound. N/ Oxidation of the 17-hydroxyl group takes place in a known manner, for instance by the Oppenauer method or with chromium trioxide. The alkylation in 17-position R1O Jon 50 can be performed by adding to the 17-keto-group of the in which relative compound a metal derivative of a saturated or R=a hydrocarbon radical, unsaturated hydrocarbon. The metal derivative may be a Ra=hydrogen, or an acyl group, and Grignard compound, for example the magnesium bromide R=hydrogen, a lower alkyl or lower alkenyl group, of the relative hydrocrabon or an alkyl lithium compound. 55 A special performance of the alkylation for the prepara reducing these compounds by a method known per se to tion of the 17-hydroxy-17-alkynyl compounds consists in the corresponding A2.5(10) - 3-alkoxy-7a-methyl-17f8-hy that the 17-keto-steroid is reacted with a triple unsaturated droxyoestradiene compound, which may possibly be sub hydrocarbon in the presence of an alkali metal or an stituted still by a lower alkyl or alkenyl group, after which alakali metal compound, such as an alkali metal amide the 3-enol-ether group is hydrolysed by treatment with an 60 or alcoholate, or by the addition of a metal compound of acid under mild conditions for the preparation of the a triple unsaturated hydrocarbon, such as an alkali metal desired A5(10)-3-keto-7 oz-methyl compound, in which, either or alkaline earth metal compound, to the 17-keto group before or after hydrolysis of the 3-enol-ether group, the of the starting product. substituents indicated in 17-position can be introduced, if The hydrocarbon radical possibly present in the final desired. 65 products in 17-position may be for example a methyl, If the 17-alkylation takes place after hydrolysis of the ethyl, propyl, butyl, isopropyl, vinyl, propenyl, allyl, 3,340,279 3 4 methallyl, ethinyl, propynyl, propargyl, or butynyl radical. for 3 hours. Next a solution is added of 12 gm. of The secondary or tertiary 17-hydroxy-steroids prepared 7a. - methyl - 17 -keto - 3 - methoxy-A2,5(10)-oestradiene by the processes described above can be esterified, if de in 60 ml. of tetrahydrofurane and 60 ml. of benzene, after sired. In the esterification inorganic acids, such as phos which acetylene is bubbled through for another 3 hours phoric acids, or saturated or unsaturated organic car at O C. - boxylic acids with 1-18 carbon atoms, can be applied. The reaction mixture is kept at room temperature for The preparation of these esters can take place by a 1 night, after which 60 ml. of ice water are added at 0° C. method known per se by reaction of the 17-hydroxy in nitrogen atmosphere. The solvents are removed by steroid with the relative acid or the anhydride or halide steam distillation. The crude crystal mass is next sucked thereof. 10 off, washed with water and dried. Next the residue is As examples of organic carboxylic acids to be used dissolved in 60 ml. of methanol after which 7 gm. of in the esterification are mentioned: formic acid, acetic oxalic acid in 120 ml. of distilled water are added. After acid, propionic acid, butyric acid, valeric acid, capric acid, 2% hours' stirring at 16 C. 300 ml. of water are added. undecylic acid, lauric acid, tridecylic acid, myristic acid, After sucking off, washing and drying the crystal mass is pentadecylic acid, oleic acid, palmitic acid, stearic acid, 15 chromatographed over silicagel to obtain the 7a-methyl arachic acid, behemic acid, lignoceric acid, cerotinic acid, 17 oz-ethnyl-178-hydroxy-3-keto-A5(10)-oestrene. mentanic acid, myricinic acid, trimethyl acetic acid, di By replacing the potassium acetylide by methyl mag ethyl acetic acid, hexahydrobenzoic acid, cyclopenityl nesium bromide, propyl magnesium chloride or allyl mag propionic acid, cyclohexyl butyric acid, cyclohexyl pro nesium bromide the corresponding 17 oz-methyl, 17 oz-propyl pionic acid, citronelic acid, undecylenic acid, erucic acid, 20 and 17a-allyl compounds are obtained. benzoic acid, phenyl acetic acid, phenyl propionic acid, phenyl butyric acid, malonic acid, succinic acid, glutaric Example III acid, pimelic acid and tartaric acid. To a solution of 2 gm. of 7a-methyl-17a-ethinyl-176 The compounds according to the invention have very hydroxy-3-keto-A5(10)-oestrene in 50 ml. of ethylacetate valuable biological properties. They exert androgenic, 25 is added 0.4 gm. of pre-hydrated palladium on barium sul anabolic, estrogenic, gonad-inhibiting and ovulation phate (5%) in 10 ml. of ethylacetate. inhibiting activities. After the required hydrogen has been taken up the cat These compounds can be administered parenterally or alyst is filtered off and washed with ethylacetate. After orally in the form of suspensions, solutions, emulsions or evaporation in vacuo chromatography takes place over Solid pharmaceutical dosage unit forms, such as tablets, 30 silicagel to obtain the 7 oz-methyl-17a-ethyl-176-hydroxy pills and coated tablets, usually after having been mixed 3-keto-A5(10)-oestrene. with auxiliary substances, or, if desired, other active Esterification of this compound yielded the 17-acetate, components. the 17-oenantate, the 17-laurate, the 176-phenylpropio The invention is illustrated further by the following nate and the 17-succinate. examples: 35 If the hydrogenation is stopped after the half of the - Example I above quantity hydrogen has been taken up A5(10)-3-keto 7a-methyl-176-hydroxy-17a-vinyl-oestrene is obtained. Two grams of 7a - methyl- oestradiol-3-methylether, dissolved in 60 ml of ether, are added to 60 ml. of liquid Example IV ammonia. At -60° C.