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3,080,400‘ United States Patent 0 ” Patented Mar. 5, 1963 2 3. The process set forth above is. illustratedvby the follow ing series of reactions: 3,080,400 Z-HYDROXYME I‘HYL ANDROSTANES Albert Bowers, John Edwards, and James C. Orr, all of OH OH l_....R5 Mexico City, Mexico, assignors, by mesne assignments, lung to Syntax Corporation, a corporation of Panama No Drawing. Filed Aug. 3, 1961, Ser. No. 128,972 Claims priority, application Mexico Mar. 20, 1961 21 Claims. (Cl. 260-3975) The present invention relates to certain new cyclopen tanophenanthrene derivatives and to a method for the 10 preparation of the same. More particularly, our invention relates to the novel 20c n R OHC—|/\ b. Home" ii (I) H }'I i (In and Z?-hydroxymethyl, alkoxymethyl, aralkoxymethyl and acyloxymethyl derivatives of androstan-17?-ol, which may further possess a l7a-alkyl, alkenyl or alkynyl group; it 15 also comprises the preparation of the esters of such com 0R1 /\ ""R’ pounds and the corresponding l9-nor-derivatives. RI l Such compounds are powerful anabolic agents having a favorable anabolic-androgenic ratio, they help to increase the protein metabolism and the deposition of calcium on 20 R4OHnC-- l p / i I (In) the bone tissue; they further show anti-estrogenic activity, lower the cholesterol level in the blood and inhibit the secretion of gonadotropins by the pituitary gland. The l7a-alkenyl and l7a-alkynyl compounds further It In the above formulas R and R1 have the same meaning exhibit progestational activity. expressed previously; R‘1 represents an acyl group of less The novel compounds object of our invention are repre than 12 carbon atoms and R5 represents hydrogen or sented by the following formula: alkyl. OBl fl In practice, a solution of a 2-formyl-A2-androsten-17B 30 ol (I:R=Me), prepared as described in our copending patent application Serial No. 128,974, in ether, dioxane or a mixture of both solvents, is reduced with an alkali metal, preferably lithium, in liquid ammonia, under an hydrous conditions, followed immediately by the destruc 35 tion of the complex formed with a proton donor such as methanol; there is thus produced in good yield the cor responding 2a-hy-droxymethyl compound (II:R=Me). In the above formula, R represents hydrogen or methyl; R1 represents hydrogen or an acyl group derived from Esteri?cation of such compounds with anhydrides or chlo rides derived from carboxylic acids of 1 to 12 carbon a carboxylic acid of 1 to 12 carbon atoms; R2 represents 40 atoms in pyridine or benzene solution produces the 2,17 hydrogen, a lower alkyl, alkenyl or alkynyl group such as diesters (III: R=Me, R5=hydrogen) or 2~monoesters methyl, ethyl, propyl, vinyl, ethynyl or propynyl; R3 rep (III: R=Me, R5=alkyl). The C-2 monoesters may be resents hydrogen, a lower alkyl group of 1 to 8 carbon esteri?ed at C-l7 with the same or with a different acid atoms, a lower aralkyl group of up to 8 carbon atoms or anhydride or chloride, in benzene solution and in the an acyl group derived from a carboxylic acid of 1 to 12 presence of p-toluenesulfonic acid. carbon atoms. The wavy line at C-2 indicates the a 45 The C-17 monoesters are obtained by selective saponi or B con?guration for the substituent at such position. ?cation of the 2-acyloxymethyl group of the 2,17-diesters. The acyl groups referred to above, derive from a car The 2u-hydroxymethyl and acyloxymethyl androstanes boxylic acid of less than 12 carbon atoms, saturated or un having a l7a-alkenyl or alkynyl group are obtained by the saturated, of straight, branched, cyclic or mixed cyclic method illustrated by the following series of reactions: aliphatic chain, substituted or not with hydroxy, lower al 50 koxy such as methoxy, amino, halogen or other groups; typical such esters are the acetate, propionate, butyrate, valerate, hemisuccinate, enanthate, caproate, benzoate, undecenoate, trimethylacetate, phenoxyacetate, cyclopent ylpropionate and ?-chloropropionate. In our copending patent application Serial No. 128,974, ?led of even date, there is described the preparation of 2 AOOHQO" Reid mid AcOHzC-— / —) formyl-Alandrostenes starting from 2-alkoxymethylene derivatives of dihydroallotestosterone, of 19-nor-dihydro allotestosterone as well as of their 17a-alkenyl, alkynyl or 60 1'1 (IV) it (v) alkyl substituted derivatives, which upon reduction with a double metal hydride produce the corresponding 3-hy droxy compounds; on further treatment with acid, the latter give rise to the formation of the 2-formyl-A2-an drostenes and l9-nor-androstenes. 65 The novel compounds object of the present invention possessing a Z-hydroxymethyl group in the tit-con?guration and further having a l7a-alkyl group, are obtained by re R4OH2C.. duction with an alkali metal in liquid ammonia of the 2-formyl-17e-hydroxy-A2-androstenes and of their 19-nor 70 analogs; by esteri?cation of such compounds there are obtained the corresponding mono- and di-esters. OR1 OH ‘guru R Horne-- l--—R° R / ,____ 1’; (VII) it (W) 8,080,400 4 3 - In the above formulas, R, R1 and R4 have the same meaning set forth above; R6 represents a lower alkenyl or alkynyl group and Ac represents the acetyl group. ‘ In practicing the process outlined above, 2a-hydroxy 0 R1 L....R2 methyl-androstan-IZB-ol (II: R=Me, R5=hydrogen) is selectively acetylated at C-2 with approximately 1 molar equivalent of .acetic anhydride in pyridine solution and R Pl I at low temperature, preferably between ‘0° and 5° C., to produce 2a-acetoXymethyl-androstan-175-01 (IV: momo R-rr-Me); oxidation of the latter with chromic acid in 10 acetone or acetic acid produces Za-acetoxymethyl-andro stan-l7-one (V: R=Me). By treatment of the latter a (XIV) compound with sodium or potassium acetylide, or with the sodium or potassium salt of another lower alkyne, In the above .formulas, R, R1, R2 and R4 have the there are obtained the Za-hydroxymethyl-Hot-alkynyl 15 same meaning set forth previously; Ac represents the compounds (VI: R=Me, R6=alkynyl), which upon catalytic hydrogenation in the presence of a palladium acetyl radical. In practicing the process outlined above, 2-hydroxy catalyst, preferably palladium on calcium carbonate, and in pyridine solution, produce the corresponding 170c methyl-M-androsten-17,8-ol or its corresponding 19-nor derivative (VIII), is obtained by reducing with sodium alkenyl derivatives (VI: R=Me, Rbalkenyl). 20 borohydride Z-fOrmyl-AZ-androsten-175-01 and 2-forn1yl Alternatively, the 17a-alkenyl and alkynyl compounds 19-nor-A2-androsten-175-01 as described in our patent maybe obtained by treating 2a-acetoxymethyl-androstan application Serial No. 128,974, ?led of even date. By 17-one (V: R=Me) with an alkenyl or alkynyl mag hydrogenation of such compounds in the presence of a nesium bromide, with simultaneous saponi?cation of the acetoxymethyl group. palladium catalyst, such as palladium on charcoal, pal The mono- and di-esters of these compounds (VII) are obtained in accordance with the methods of esteri?cation bonate, with the uptake of one molar equivalent of hy drogen, there are obtained 2i8-hydroxymethybandrostan? ladium on barium sulfate or palladium on calcium car described previously for the 17u-alkyl derivatives. 175-01 and ZQ-hydroxymethyl-l9-noraandrostan-175-01 In the same manner, the processes which we have just (IX). Suitable solvents for this hydrogenation are the ‘described are applied to the 2-formyl-19-nor-A2-andro 30 aliphatic alcohols such as methanol, ethanol or pro~ stenes, thus producing 2a-hydroxymethyl-19-nor-andro stan-17/3-ol, the corresponding l7a-alkyl, alkenyl and panol; ethyl acetate, dioxane, tetrahydrofuran, etc. Modi?cations in the reaction temperature, pressure and catalyst used do not vary considerably the course of the reaction. alkynyl derivatives as well as the mono- and di-esters of such compounds. The novel compounds possessing a Zp-hydwxymethyl 35 or 2,8-acyloxymethyl group are obtained by the process illustrated by the following series of reactions: By esteri?cation of the Ze-hydrOXymethyI-androstanes by conventional methods with anhydrides or chlorides of carboxylic acids of the type set forth above, there are obtained the 2,17-diesters (X), which by selective hy (‘3H l R ?H l EOHaC- R II drolysis of the acyloxymethyl group at C~2 afford the 40 l7-monoesters. By treatment of 2/3-hydroxymethyl-androstan-l7;3~0l or its 19-nor-derivative with approximately 1 molar equiv alent of acetic anhydride in pyridine solution and at room vtemperature, preferably between 0° and 5° 0, there are HOHzC ' \J ft 45 (vm) r'r / (RH AcOHzC- R dation with an 8N solution of chromic acid, in acetone solution, or with 1.1 equivalents of chromic acid in acetic (IX) l acid, furnish the l7-ketones (XII). 50 . _ For preparing the 17u-alkyl, alkenyl or alkynyl deriva tives (XIII), 2B-acetoxymethyl-androstan-l7-one or its 19-nor derivative is treated with an organometallic halide, ORl R‘OHzC- RI ‘obtained 2B-acetoxymethyl-androstan-17/3-01 and ZB-ace toxymethyl-l9-nor-androstan-17,6-01 (XI) which by oxi at the re?ux temperature for 2 to 5 hours or overnight at room temperature. Adequate solvents for this reac 55 tion are the aromatic hydrocarbons, such as benzene, toluene or xylene, or other organic solvents inert to this reaction such as ether or tetrahydrofuran. In this man ner the l7-keto group is converted into the l7?-hydroxy 15 (XI) 17a-alkyl, 17,8-hydroxy-17a-alkenyl or l7l8-hydroxy-l7a 60 alkynyl groupings, according to the Grignard reagent em ployed for the reaction, simultaneously, the Z?-acetoxy methyl group is hydrolyzed to produce the 17oL-sllb stituted Z?-hydroxymethyl-l7l9-hydroxyaandrostanes. For example, by reacting Z?-acetoxymethyl-androstan-17-one with methyl~magnesium bromide, there is obtained 2/3~ hydroxymethyl-l7u-methyl-androstan-1713-01. AOOHzC By esteri?cation of the Not-substituted 2?-hydroxy methyl-androstanes and 19-nor-androstanes, by conven tional methods, there are obtained the C-2 monoesters, which on treatment with the same or a different acid anhydride or chloride in benzene solution and in the presence of p-toluenesulfonic acid, produce the diesters. ; The selective hydrolysis of the 2,6-acy1oxymethyl group produces the 177II1OI1O€SI€I'S. Alternatively,'the l7d-Valky1 substituted compounds'may 6 Example 11 By following the method of the preceding example, but using 2-formyl-19-nor-A2-androsten-1713-01 as starting be obtained by treating the 17-ketones (XII) with an alkyl-lithium. The 17a-alkynyl substituted compounds. are also ob tained by treating 2/3-acetoxymethyl-androstan-17-one or material, there was obtained 2a-hydroxymethyl-19-n0r androstan-17B-ol and its corresponding diacetate. its l9-nor derivative with sodium or potassium acetylide or with the sodium or potassium salt of another alkine. Example III By partial hydrogenation of the 2/3-hyroxymethy1-17a alkynyl-17-?-hydroxyandrostanes and 19-nor-androstanes, A solution of 5 g. of 2-hydroxymethyl-androstan-1718-01 in‘ 20 cc. of pyridine was cooled at 0° C., treated with 1.8 on calcium carbonate, and using an amine as solvent, 10 g. of: acetic anhydride (1.1 equivalents) and allowed to re preferably pyridine, there are obtained the 2,8-hydroxy act at 0° C., for 24 hours; it was then poured into water, methyl-l7a-alkenyl-17?-hydroxy-androstanes and 19-nor extracted with ethyl acetate and the extract was washed to audrostanes. neutral, dried and evaporated to dryness. The residue The novel 20: and ZB-alkoxy and 2a- and ZB-aralkoxy was chromatographed on washed alumina, thus affording in the presence of a palladium catalyst such as palladium compounds object of our invention are obtained by the 15 method illustrated by the following equation: 2a-acetoxy-methyl-androstan-175-01. A stirred solution of 3 g. of the above compound in 60 cc. of acetone was treated with 5 cc. of an 8 N solu tion of chromic acid (prepared in 23% sulfuric acid) and the mixture was kept at room temperature for 10 minutes. 20 At the end of this time the mixture was poured into water and the precipitate formed was collected, thus giving 2o¢~ acetoxymethyl-androstan-17-one. A solution of 2 g. of the above ketone in 60 cc. of anhydrous benzene was added under an atmosphere of 25 nitrogen to a solution of potassium t-amyloxide, prepared In the above formulas, ‘R, R1 and R2 have the same meaning set forth previously; R’7 represents a lower alkyl previously from 1.4 g. of potassium and 30 cc. of t-amyl alcohol. A slow stream of puri?ed acetylene was intro duced into the resulting solution for 40 hours and the solution was then poured into ice water and extracted with or aralkyl group; the wavy line indicates the a or is con 30 several portions of benzene. ?guration for the substituent at C—2. -In practicing the process outlined above, a 17-ester of Z-hydroxymethyl-androstan-1713-01, which may further possess a substituent at C-17cl. of the type set forth previously, or the corresponding 19-nor derivatives (XV), is reacted at room temperature with an excess of an ether solution of a diazoalkane, such as diazomethane or diazoethane, and in the presence of a catalyst, such as boron tri?uoride or aluminum chloride, and there are The combined extract was washed‘ to neutral, the organic layer was dried over an hydrous sodium sulfate and evaporated to dryness under vacuum. The residue was chromatographed on 50 times its weight of washed alumina and the crystalline fractions were recrystallized from acetone-hexane, thus furnishing Zu-hydroxyrnethyl-l7a-ethynyl-androstan-l7-5-01. A mixture of 500 mg. of the above compound, 2 cc. of pyridine and 1 cc. of acetic anhydride was heated on the steam bath for 1 hour, poured into water and the precipi produced the Z-methoxymethyl or 2-ethoxymethyl deriva 40 tate formed was collected. There was thus obtained 2a tives (XVI: R7=Me, Et; R1=acyl). Saponi?cation of these compounds by conventional methods affords the free ethers. Alternatively, the etheri?cation may be effected by re acting at the re?ux temperature the 2-hydroxymethyl compounds of Formula XV with an alkyl or aralkyl halide, preferably with an alkyl or aralkyl iodide, in an organic solvent such as acetone and in the presence of a base such. as potassium carbonate, or by treatment with an alkyl sulfate in acetone solution and in the presence of a base, preferably potassium hydroxide, at room tempera ture. The following examples serve to illustrate but are not intended to limit the scope of the invention: Example I A solution of 5 g. of 2-formyl-A2-androsten-1713-01 in 100 cc. of a mixture of dioxane and ether (1:1) was slow ly added to a stirred solution of 1.5 g. of lithium metal in lacetoxymethyl-l7a~ethynyl-androstan-17,8-01. In the same manner 2a-hydroxymehyl-17-nor-andro stan-17?-ol was converted into 2a-acetoxymethyl-19-nor androstan-17?-ol, 2a-acetoxymethyl-19-r10r-andro-stan-17 one, Za-hydroxymethyl-17a-ethynyl-1-9=nor-androstan-17/3 01 and ?nally into Za-acetoxymethyl-17a-ethynyl-19-nor androstan-UB-ol. _ Example IV In accordance with the method of reduction described in Example I, .there was treated 5 g. of 2-formyl-17a rnethyl-Az-and-rosten-17/3-01 and 5 g. of 2-formyl-17a methyl-l9-nor-A2-androsten-1713-01 with lithium in liquid ammonia to produce 2a-hydrroxymethyl-17or-methyl-an~ drostan-17/3-ol and its corresponding 1'9-nor analog. From a solution of 1 g. of Za-hydrOXymethyl-I7a-meth~ yl-androstan-17?-ol in 130 cc. of benzene free of thio phene there was distilled approximately 30 cc. in order to remove moisture; there was then added 0.52 cc. of py 750 cc. of liquid ammonia. At the end of the addition 60 ridine and 1.5 cc. of undecenoyl chloride and the mixture was re?uxed for 1 hour [and evaporated to dryness; the there was added dropwise 10 cc. of methanol until the residue was chromatographed on 30 g. of washed alumina, blue color of the solution was discharged. The ammonia was evaporated, water was added to the residue and the product was extracted with ether; the organic extract was washed to neutral, dried over anhydrous sodium sulfate thusv yielding 2a-undecenoyloxymethyl-17a-methyl-an drostan-17?-ol. Example V and evaporated to dryness. Chromatography of the resi A solution of 500 mg. of 2a-hydroxymethyl-androstan~ due on 250 g. of washed alumina, followed by recrystal lization of the solid fractions from acetone-hexane afford 175-01 in 2 cc. of pyridine was treated with 1 cc. of caproic anhydride and the mixture was kept overnight at room ed 2a-hydroxymethyl-androstan-1719-01. temperature, then poured into water and the precipitate A mixture of 1 g. of the above compound, 4 cc. of 70 formed was collected, thus giving the caproa-te of 2-cap ronoxymethyl-androstan-175-01. pyridine and 2 cc. of acetic anhydride was heated on the steam bath for 1 hour, then poured into water and the precipitate formed was collected, washed with water to By the same methods, but using propionic, valeric and cyclopentyl-propionic anhydrides as esterifying agents neutral and dried. Crystallization from acetone-hexane there were obtained the corresponding diesters of 2a-hy yielded 2a-acetoxymethyl-androstan-1713-01 acetate. droxymethylaandrostan-17,8-01. 3,080,400 Example VI pyridine and 5 cc. of propionic anhydride was allowed A mixture of 1 g. of 2a-hydroxymethyl-17a-methyl-an drostan-IZB-ol, 50 cc. of benzene, 2 cc. of acetic anhy to react at room temperature overnight and then poured into water. The precipitate formed was collected by dride and 500 mg. of p-toluenesulfonic acid was kept at room temperature for 48 hours, then diluted with water and the benzene layer was separated, washed with 5% ?ltration to give the propionate of 2,8-propionoxymethyl androstan -17?-ol. By the same method of esteri?cation, but using acetic anhydride and caproic anhydride as esterifying agents sodium carbonate solution and water, dried over an there were obtained the acetate of Z?-acetoxymethyl hydrous sodium sulfate and evaporated to dryness under androstan-17?-ol and the caproate of Z?-capronoxymeth reduced pressure. By chromatography of the residue fol lowed by crystallization of the solid fractions from ace 10 yl-androstan-17B-ol. ' Example X tone-ether there was obtained the acetate of 2a-acetoxy A solution of 15 g. of 2/8-hydroxymethyl-androstan methyl-17a-methyl-androstan-175-01. 1713-01 in 60 cc. of pyridine was cooled to 0° C. and In the same manner, but using propionic, caproic, un - treated with 5.5 ‘g. of acetic anhydride (1.1 equivalents). decenoic and cyclopentylpropionic anhydrides as esterify The mixture was allowed to react at 0° C. for 18 hours, ing agents (of the latter two anhydrides, twice the amount then poured into water and extracted with ethyl acetate. was employed), there were obtained the propionate of 2a propionoxymethyl-17a-methyl-androstan-1718-01, the cap roate of 2ot-capronoxymethyl-17a-methyl-androstan-1715’ ol, the undecenoate of 2a-undecenoyloxymethyl-andro stan-17B-ol and the cyclopentylpropionate of Zen-cyclo pentylpropionoxymethyl-androstan-173-01. Example VII A solution of 750 mg. of 2a-hydroxymethyl-17a-ethy The extract was washed to neutral, dried, evaporated to dryness and the residue was chromatographed on washed alumina, thus producing 213-acetoxymethyl-androstan 175-01. A stirred solution of 10 g. of the above com pound in 100 cc. of acetic acid was treated dropwise with a solution of 2.5 g. of chromic acid in 25 cc. of 80% acetic acid at a temperature between 15 and 20° C. The mixture was kept standing at room temperature for ny1-androstan-17?-ol in 20 cc. of pyridine was hydroge 25 1 hour, poured into ice cold salt solution and the precipi~ nated at room temperature and atmospheric pressure us tate formed was collected by ?ltration and washed with ing 0.2 g. of 5% palladium on calcium carbonate catalyst (which had been previously reduced). After the uptake Water to neutral, thus yielding Z?-acetoxyrnethyl-andros tan-17-one, which was puri?ed by crystallization from chloroform-methanol. of 1 molar equivalent of hydrogen the catalyst was re moved by ?ltration and the ?ltrate was evaporated to 30' A solution of 5 g. of 2,8-acetoxymethyl-androstan-17 dryness under vacuum. The residue was dissolved in one in 100 cc. of anhydrous benzenefree of thiophene ethyl acetate, washed with hydrochloric acid to complete ly remove the pyridine and ?nally with water to neutral, dried and concentrated to a small volume. Crystalliza tion from ethyl acetate-hexane atforded 2a-hydroxymeth yl-17a-vinyl-androstan-175-01. was added little by little to 25 cc. of a 4N solution of methyl magnesium bromide in ether and the mixture was re?uxed under anhydrous conditions for 3 hours; after cooling, the mixture was cautiously poured into water, acidi?ed with hydrochloric acid and the benzene layer A mixture of 1 g. of 2ot-hydroxymethyl-17a-vinyl-an drostan-17p-ol, 10 cc. of pyridine and 1 cc. of acetyl chlo ride was kept at room temperature for 36 hours and then was separated. The aqueous phase was extracted sev eral times with ethyl acetate and the extract was corn lbelow 60° C. By crystallization of the residue from methylene chloride-hexane there was obtained 2a-acetoxy fate and evaporated to dryness under reduced pressure. Crystallization of the residue from acetone-hexane af bined with the benzene solution. The organic solution the solvent was removed under vacuum at a temperature 40 was washed to neutral, dried over anhydrous sodium sul methyl-17a-vinyl-androstan-1718-01. forded 2/3-hydroxymethyl-17a-methyl-androstan-175-01. ‘ By the same method, but using 2a-hydroxymethy1-17a A mixture of 2.5 g. of the above compound, 100 cc. were successively obtained Za-hydroxymethyl-l7a-vinyl p-toluenesulfonic acid was kept at room temperature for ethynyl-19-nor-androstan-l7?-ol as starting material there 45 of acetic acid, 50 cc. of acetic anhydride and 2.5 g. of 19-nor-androstan-17p-ol and 2a-acetoxymethyl-17a-vinyl 19-nor-androstan-17p-ol. 18 hours, then poured into water, heated for 30 minutes on the steam bath to hydrolyze the excess of reagent and the precipitate formed was collected by ?ltration, and Example VIII 1 g. of the acetate of 2e-acetoxymethyl-17a-methyl-an drostan-17/3-ol was dissolved in 50 cc. of a 1% solution 50 washed with water to neutral, thus producing the acetate of 2,8-acetoxyrnethyl-17a-methyl-androstan-1718-01. By selective saponi?cation by treatment with 1% methanolic potassium hydroxide solution in accordance of potassium hydroxide in methanol and the mixture was kept at room temperature for 4 hours, then neutralized with the method of Example VIII, there was obtained the with a few drops of acetic acid, concentrated to a small 55 17-acetate of 2,8-hydroxymethyl-17a-methyl-androstan volume and diluted with water. The precipitate formed 1713-01. was collected, washed, dried and crystallized from ace Example XI tone-ether, thus furnishing the 17-acetate of 2a-hydroxy methyl-17a-methyl-androstan-17?-ol. ' By the same method the dicaproate, the dipropionate and the dicyclopentylpropionate of 17a-methyl-androstan 17;.8-01, obtained in Example VI, were converted into the corresponding 17-monoesters. Example IX A solution of 20 g. of Z-hydroxymethyl-M-androsten A solution of 5 g. of Z?-acetoxymethyl-androstan-17 one in 100 cc. of anhydrous ether was added dropwise to a solution of propargyl magnesium bromide (prepared from 6.8 g. of propargyl bromide, 1.4 g. of magnesium and 200 cc. of ether). The mixture was re?uxed with stirring for 5 hours, cooled and poured into 500 cc. of 5% ammonium chloride solution; the ether layer was separated, washed with water to neutral, dried over an hydrous sodium sulfate and evaporated to dryness under ‘1718-01 in 400 cc. of ethyl acetate was hydrogenated at vacuum. Crystallization of the residue from methanol room temperature and atmospheric pressure in the pres furnished 2,8-hydroxymethyl - 17oz - propargyl-androstan ence of 2 g. of 5% palladium on charcoal catalyst which had been previously reduced. After the uptake of 1 molar 70 175-01. 1 g. of the above compound was dissolved in 20 cc. equivalent of hydrogen the catalyst was removed by ?ltra of benzene and treated with 2 cc. of propionic anhydride tion through celite and the ?ltrate was evaporated to dry and 0.5 g. of p-toluenesulfonic acid. The mixture was kept ness. Chystallization of the residue from methylene chlo overnight at room temperature, then diluted with water ride-hexane afforded ZB-hydroxymethyl-androstan-17,8-01. A mixture of 1 g. of the above compound, 5 cc. of is and stirred for 30 minutes to hydrolyze the excess of re 3,080,400 10 agent; the benzene layer was separated and washed with 5% sodium carbonate solution and ?nally with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Chromatography of the residue on washed alumina followed by crystal lization of the solid fractions from acetone-hexane af obtained Z?-acetoxymethyl - l9 - nor - androstan - 17-,8 - 01, forded the propionate of ZB-propionoxymethyl-l7a-pro nor-androstan-l75-ol. which on oxidation with chromic acid in acetic acid a?orded 2/8-acetoxymethyl-l9-nor-androstan-17-one. 5 g. of the above compound was treated with methyl magnesium bromide in accordance with the method of Example X, thus giving 2,8-hydroxymethyl-17/3-methyl-l9 In the same manner, but using ethyl, vinyl and ethynyl pargyl-androstan-lmeol. magnesium bromide as alkylating agents, there were ob Example XII A solution of 2 g. of 2IS-acetoxymethyl-androstan-l7 10 one in 60 cc. of anhydrous benzene was added under an tained, respectively: 2?-hydroxymethyl-l7a-ethyl-l9-nor andr0stan-1718-o1, 2?~hydroxyrnethyl-l7a - vinyl - l9 - nor androstan-l7?-ol and 2/3-hydroxymethyl-l7a-ethynyl-19 nor-androstan-UB-ol. atmosphere of nitrogen to a solution of potassium amyl oxide previously prepared from 1.4 g. of potassium in 30 cc. of amyl alcohol. A slow stream of puri?ed acetyl Example XVI A solution of l g. of the caproate of 2a-hydroxymethyl~ ene was then introduced into the resulting solution for 15 l7a-methyl-androstan-l7?-ol, obtained in accordance with 40 hours and the solution was then poured into ice water Example VIII, in 100 cc. of ether was cooled to 0-5° C. and extracted with several portions of benzene. The and treated with an ether solution of diazomethane (pre combined extract was washed to neutral, the organic pared from 5v g. of nitrosomethylurea) and 3 drops of layer was dried over anhydrous sodium sulfate and evapo rated to dryness under vacuum. The residue was chro 20 recently distilled borontri?uoride etherate. The mixture was kept at room temperature for 1 hour, treated with matographed on 50 times its weight of washed alumina a few drops of acetic acid to destroy the excess of diazo and the solid fractions were recrystallized from acetone methane and evaporated to dryness, thus giving the hexane, thus yielding Z?-hydroxymethyl - 17oz - ethynyl caproate of 2a-methoxymethyl-l7a-methyl-androstan-17B androstan-17pl-ol. A mixture of 500 mg. of the above compound, 2 cc. 25 ol. 5 A solution of 500 mg. of the above compound in 50 cc. of methanol was treated with a solution of 500 mg. of potassium hydroxide in 1 cc. of water and the mixture precipitate formed was collected, thus giving 2?-acetoxy— was kept overnight at room temperature; it was then methyl-l7a-ethynyl-androstan-17,8-01. 30 neutralized with acetic acid, concentrated to a small vol Example XIII ume and diluted with water until complete precipitation A solution of 2 g. of 2/3-hydroxymethyl-l7u-ethynyl of the product, which was collected and crystallized from androstan-l7B-ol in 50 cc. of pyridine was hydrogenated methylene chloride-hexane, thus furnishing 2et-methoxy at room temperature and atmospheric pressure in the methyl-17a-methyl-androstan-176-01. presence of 0.6 g. of 5% palladium on calcium carbonate 35 Example XVII of pyridine and 1 cc. of acetic anhydride was heated for 1 hour on the steam bath and poured into water. The (which had been previously reduced). After the uptake A mixture of 2 g. of ZB-hydroxymethyl-l7a-vinyl-l9 nor-androstan-l7?-ol, 100 cc. of anhydrous acetone, 10 cc. of methyl iodide and 2v g. of anhydrous potassium ness under vacuum. The residue was dissolved in ethyl acetate, washed with hydrochloric acid to remove all of 40 carbonate was re?uxed for 48 hours under anhydrous of 1 molar equivalent of hydrogen the catalyst was re moved by ?ltration and the ?ltrate was evaporated to dry conditions. the pyridine and ?nally with water to neutral, dried and concentrated to a small volume. At the end of this time the mixture was poured into water, extracted with ethyl acetate and the Crystallization from organic extract was washed with water, dried over an ethyl acetate-hexane furnished 2,8-hydroxymethyl-l7a hydrous sodium sulfate and evaporated to dryness under The residue was puri?ed by chromatography on tic anhydride in pyridine gave Z?-acetoxymethyl-17a-vinyl 4:5 vacuum. washed alumina, thus giving 2/3-methoxymethyl-l7a-vinyl vinyl-androstan-l7/3-ol. Subsequent acetylation with ace androstan-l7?-ol. l9-nor-androstan-17?-ol. benzene, 2 cc. of cyclopentylpropionic anhydride and 250 pound with propionic anhydride in benzene solution and A mixture of 500 mg. of the above compound, 25 cc. of By esteri?cation of this com in the presence of p-toluenesulfonic acid there was ob mg. of p-toluenesulfonic acid was kept standing at room temperature for 48 hours and then diluted with water and 50 tained the propionate of ZB-methoxymethyl-l7a-vinyl-19 nor-androstan-l7?-o-l. stirred for 30 minutes to hydrolyze the excess of reagent; Example XVIII the benzene layer was separated, washed to neutral, dried By following the method of the preceding example, but over anhydrous sodium sulfate and evaporated to dry using ethyl, propyl or benzyl iodide instead of methyl ness. Crystallization from acetone-ether afforded the cyclopentylpropionate of Z?-acetoxy-methyl-l7tx-vinyl 55 iodide, andro-stan-l7B-ol. Example XIV By following the method of hydrogenation described in the preceding example, 500 mg. of the propionate of 2/3 propionoxymethyl-17a-propargyl-androstan - 17B - 01 was 60 converted into the propionate of 2B—propionoxyrnethyl l7a-propenyl-androstan-175-01. Example XV A suspension of 10 g. of Z-hydroxymethyl-l9-nor-A2 androsten-l75-ol in 100 cc. of methanol was added to a 65 the acetate of Z?-hydroxymethyl-l7a-methyl androstan-l7B-ol, obtained by the method of Example X, was converted into Z?-ethoxymethyl-l7rx-methyl-andro stan-l7?-ol acetate, ZB-propoxymethyl-17a-methyl-andro stan-l7B-ol acetate and 2,8-benzyloxymethyl-l7a-methyl androstan-l7B-ol acetate. By subsequent saponi?cation of these compounds, in accordance with the method of Ex ample XVI, there were obtained the respective free com pounds. Example XIX A mixture of 1 g. of the acetate of ZB-acetoxymethyl androstan-l7?-ol and 50 cc. of 1% potassium hydroxide suspension of 10% palladium on calcium carbonate which solution was kept standing at 0° C. for 2 hours; it was had been previously reduced and the mixture was hy then neutralized with a few drops of acetic acid, poured drogenated at room temperature and atmospheric pres into water and extracted with ethyl acetate; the organic sure until the equivalent of 1 mol of hydrogen had been absorbed. The catalyst was removed by ?ltration and 70 extract was washed to neutral, dried and evaporated to dryness under vacuum. Chromatography of the residue the ?ltrate was evaporated until crystallization started, thus aifording ZB-hydroxymethyl-l9-nor-androstan-l7B-ol. afforded the l7-acetate of Z?-hydroxymethyl-androstan 175-01. The above compound was treated with 1.1 molar equiv 500 mg. of the above compound was treated with an alents of acetic anhydride in pyridine, at 0° C., in accord ance with the method of Example X. There was thus 75 excess of diazomethane, in the presence of borontri?uo 3,080,400 12 11 ride, folowing the method of Example XVI, to produce wherein R is selected from the group consisting of hy the acetate of Z?-methoxymethyl-androstan-17,8-01. drogen and methyl; R1 is selected from the group con . A solution of 300 mg. of the above compound in 501 cc. of methanol was re?uxed for 1 hour with 159 mg. sisting of hydrogen and a hydrocarbon carboxylic acyl of potassium hydroxide, cooled, poured into water and the group consisting of hydrogen, lower alkyl, lower group of less than 12 carbon atoms; R2 is selected from the precipitate'formed Was collected and washed to neu alkenyl and lower alkynyl and R3 is selected from the tral, thus giving Zti-methoxymethyl-androstan-175-01. . Example XX group consisting of an alkyl group containing from 1 to 8 carbon atoms, and aralkyl group containing up to 8 carbon atoms and a hydrocarbon carboxylic acyl group ' A solution of} 250 mg. of the above ether in 1 cc. of 10 of less than 12 carbon atoms. pyridine was treated with 0.5 cc. of benzoyl chloride ' 2. The 2-lower alkoxymethyl-androstan~17,8:01. and heated on the steam bath for 1 hour; the mixture was then cooled, poured into water and the precipitate formed was collected and recrystallized from chloroform 3. 2a-methoxymethyl-androstan-1713-01. 4. Z?-ethoxymethyl-androstan-1718-01. methanol, thus furnishing the benzoate of 2,8-methoxy 15 l6. The cyclopentylpropionate of 2a-methoxymethyl 5. 2a-methoxy-methyl-l7e-rnethy1-androstan-‘175-01. methyl-androstan-Np-ol. 17a-ethynyl-androstan-1713-01. 7. The caproate of 2u-methoxymethyl-17a-methyl~ Example XXI vandrostan-17i3-ol. There was repeated the preceding example, but using 8. The hydrocarbon carboxylic acid esters of less than the acetate of 2a-acetoxymethyl-l9-nor-androstan-l7? 20 12 carbon atoms of 2~hydroxymethyl-androstan-l7,8-01. 01 as starting material, thus obtaining successively the 179. The propionate of 2a-propionoxymethyl-androstan acetate of 2a-hydroxymethyl- l9-nor-androstan-17?-ol, the acetate of Zu-methoXymethyl-I9-nor-androstan-17B, .i710.1'1‘he caproate of 2oe-capronoxymethyl-androstan o1, 2a-methoxymethyl-19-nor-androstan-17/3-ol and the benzoate of 2a-methoxymethyl-l9-nor-androstan-1713-ol. Example XXII 11. 2a-acetoxymethyl-17u-ethynyl-androstan-175-01. ’ 12. A compound ‘of the following formula: A solution of 500 mg. of the acetate of ZB-hydroxy methyl-l7a-methyl-androstan-175-01 in 75 cc. of ether was treated with an excess of an ether solution of di azoethane in the presence of 10 mg. of aluminum chloride 30 as catalyst and the mixture was allowed to react at room temperature ?or 1 hour; the excess of reagent was de stroyed with a few drops of acetic acid and the mixture was evaporated to dryness, thus giving the acetate of 35 2?-ethoxymethyl-l7ot - methyl-androstan-Up-ol, identical with the one obtained in Example XVIII. HOHzCMN TF1 i Example XXIII By following the method of esteri?cation described in 40 Example VI, of 2 g. of 2a-acetoxymethyl-l7a-ethylny1-an H wherein R is selected from the group consisting of hydro gen and methyl; R1 is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group cyclopentylpropionate of 2a-acetoxyrnethyl-l7a-ethynyl 45 of less than 12 carbon atoms; and R2 is selected from the group consisting of hydrogen, lower alkyl, lower al androstan-17?-ol. kenyl and lower alkynyl. The above compound was selectively sapom'?ed at 13. 2-hydroxymethyl-androstan-175-01. C—2, in accordance with the method of Example VIII, f14. Z-hydroxymethyl-l9-nor-androstan-17?-ol. and the resulting 2ot-hydroxymethyl compound was l5. Z-hydroxymethyl-l7ot-ethynyl-androstan-1718-01. treated with methyl iodide in acetone and in the presence 50 drostan -17,6-ol, obtained in Example VI, was treated with cyclopentylpropionic anhydride in benzene solution and in the presence of p-toluenesulfonic acid, thus giving the cedure described in Example XVII; there was thus ?nally 16. Z-hydroxyrnethyl-17u-methyl-androstan-1713-01. 17. Z-hydroxymethyl-l7u-vinyl-androstan-17?-ol. obtained the cyclopentylpropionate of 2a-methoxymethyl 1 l8. Z-hydroxymethyl-l7ot-methyl - 19 - nor - androstan of anhydrous potassium carbonate, by following the pro 17u-ethynyl-androstan-17,3-01. We claim: 7,B'ol. “ 55 1. A compound of the following formula: 1 19. Z-hydroxymethyl-l7a-ethynyl - l9 - nor - audrostan 76-01. 20. A process for preparing a ZOL-hydroXymethyI-an drostan-17?-ol comprising reducing a 2-forn1yl-A2-andro sten-17?-ol with an alkali metal in liquid ammonia. 21. A process for preparing a Zp-hydroXymethyI-an . n15” drostan-17/3-ol comprising hydrogenating a 2-hydroxy methyl-Az-androsten-lm-ol in the presence of a palladium 3.301120 MN catalyst. 65 No references cited.