i

United States Patent Of?ce 3,409,643 Patented Nov. 5, 1968 l 2 ’ 3,409,643 choire when preparing esters atI C-17 of l7a-alkynyl-l7? PROCESS FOR THE PREPARATION OF 1711 hydroxy steroids and particularly ' ALKYNL -l7?-ALKANOYLOXY STEROIDS of those steroids which OF THE ANDROSTANE AND ESTRANE also possess functions or systems ,(e.g. 3-methoxy-A2'5(1°> SERIES , and 3-ethoxy-A3,5.-) which are highly reactive or sensitive Elliot L. Shapiro, Cedar Grove, N.J., assignor to Schering Corporation, Bloom?eld, N.J., a corporation of New hydroxyl group. Thus, Jersey preparation of 3-methoxy-17a-ethinyl-2,5(10)-esteradien . No Drawing. Filed Mar. 11, 1966, Ser. No. 533,435 17,8-01 l7_-aeetate (an intermediate in the preparation of 10 Claims. (Cl. 260-—397.5) therapeutically valuable l9-n0r steroids) via methods 10 \ known in the art involves reacting 3-methoxy-l7a-ethinyl 2,5 ( 10)-estradien-17B-ol withv acetic anhydride in pyridine ' _ABSTRACT OF THE DISCLOSURE at elevated temperatures or with acetyl chloride in pyri A novel process for the preparation of 17a-alkynyl dine. Both the aforementioned reaction mediums cause l7?-alkanoyloxy steroids of the androstane and estrane ' involving destruction of the existing series comprises subjecting a 17~keto steroid of the andro A-ring sys em such as conversion of the 3-methoxy stane and estrane series to the ' ' Azimol- sys‘em to a 3-keto-l9-nor-A4- system or to an acetylide and adding in situ to the 17a-alkynyl-l7B-hy aromatic A-ring system (i.e. 3-methox-y-A1'3'5(1°)) so that droxy metal salt intermediate thereby formed, an aeylat only a small yield of the desired 3-methoxy-l7a-ethinyl ing agent selected from the group consisting of a lower 20 2,5(10)-estradien-17,B-ol 17-acetate is formed. By my in alkanoyl anhydride and a lower alkanoyl halide. V vention, however, 3-methoxy-l7a - ethinyl-2,5(10)-estra This process advantageously performs concomitantly dien-17,B~ol l7-acetate is conveniently prepared via a one both’ an alkynation and esteri?cation reaction and pro vessel process in good yields from 3-methoxy-2,5(10) vides amethod for preparing an ester of a tertiary alcohol under mild conditions in a medium which will not effect 25 functional groups or systems which are highly reactive acetic anhydride. The 3-methoxy - 171x - ethinyl-2,5(l0) or sensitive to vigorous conditions or strongly acidic and. estradien-l7B-ol 17-acetate thereby formed, upon reaction strongly basic media. with mild acid, e.g. oxalic acid, is converted to 1711 This process is ‘of particular use in the conversion of 3~ ethinyl-5(10)-estren-17B-ol l7-acetate which when sub methoxy - 2,5 (10) - esteradien-l7-one to 3-methoxy-17a 30 jected to the action of oxygen according to procedures valuableethinyl - intermediate.2,5(10) - esteradien-l7/3-ol l7-acetate, a known, known in the art, yields lO?-hydroperoxy-l7a-ethinyl-l9 stratingnor-4-androsten-17B-ol anti-fertility activity. l7-acetate, a compound demon \ In general, when carrying out my process, an alkali This invention relates to a novel process and to novel metal acetylide, e.g., sodium acetylide, is added to a 17 intermediates produced thereby. keto steroid of the androstane and pregnane series, e.g., 5-androsten-3l8-ol 17-one and 3-methoxy-2,5(10)-estra dien-17-0ne, in a non-interfering solvent, having a high dielectric constant

and a lower alkanoyl halide. 17a-ethinyl-5-pregnene-3?,17B-diol 17-so 45 \3-methox -l7a-ethinyl-2,5 ( 10) -estradien Heretofore, the conversion of a l7-keto steroid to a 175-01 sodium salt, respectively, there is ‘added, in situ, l7a-alkynyl - 17p)- alkanoyloxy steroid involved a ,multi step process; namely, the preparation of a 17a-alkynyl 17,8-hydroxy steroid intermediate by reaction of a 17~ keto- eroid with an alkynating agent (e.g. an alkali metal 50 alkynating agent. The resulting Not-ethinyl-l7/3-alkanoyl oxy steroid, e.g., 17a-ethinyl-5-androstene-3/8,17,8-diol di the 17u-alkynyl-17?-hydroxy steroid thereby formed, and thereof under the vigorous conditions (i.e. high temperatures and/or in strongly acidic me diums) necessary ' '

operation, thus advantageously eliminating the steps of 60 preparing per se and isolating the 17a-alkynyl-l7/3-hy droxy ‘steroid intermediate required in prior art methods. Additionally, by my process, whereby an acylating agent (eg. a lower alkanoyl anhydride or a lower alka noyl halide) is added in situ to a l7a-alkynyl-l7/3-hydroxy 65 metal salt intermediate, it is now possible to prepare an ester of the tertiary alcohol at C-17 under mild condi tions (i.e. at room temperatures, and in a medium which amide, is, in effect, non-reactive, i.e. does not cause transforma as N-methyl-Z-pyrrolidone. Ethers such as tetrahydro furan and dioxane are also useful tions usually effected by strongly acidic or strongly basic as solvents for my media). The process of this invention is thus a method of process. The alkynating agents conveniently used in my process 3,409,643 4 tetrahydropyranyl ether derivatives prior to concomitant are alkali metal acetylides which term (as used through alkynation and esteri?cation at C—l7. Treatment of the out the instant speci?cation and claims) includes lithium tetrahydropyranyl ether derivatives of the 17a-alkynyl and sodium acetylide whereby, together with the in situ l7?-alka'noyloxy compounds thereby formed with dilute addition of an alkanoyl anhydride or halide, are prepared acid removes the tetrahydropyranyl ether function with l7a-ethinyl-l71S-alkanoyloxy derivatives, as well as sub ease to yield the free hydroxy analogs. Thus, for example, stituted alkali metal acetylides, and, in particular, alkyl estrene and 5-an'drosten-3p-ol-l7-one, upon reaction with substituted and halogeno-substituted alkali metal acety dihydropyran in the presence of a strong acid such as p lides, such as sodium methyl acetylide, lithium chloro toluenesulfonic acid (according to known procedures) will acetylide, and lithium bromoacetylide, whereby, together give the corresponding tetrahydropyranyl ether deriva with the in situ addition of an alkanoyl anhydride or ha 10 tives, e.g. estrone B-tetrahyd-ropyranyl ether and S-andro lide, are prepared l7a-methylethinyl-, l7a-chloroethinyl-, sten-3?-ol-l7-one 3-tetrahydropyranyl ether. Reaction of and l7a-bromoethinyl-l7?-alkanoyloxy derivatives, re each of the foregoing with sodium acetylide in dimethyl formamide followed by the in situ addition of acetic spectively.Acylating agents contemplated for use in the process anhydride will yield l7u-ethinylestradiol 3-tetra-l1ydro‘ and halides of car 15 pyranyl ether l7-acetate and l7a-ethinyl-Sandrostene-3B, boxylic carbon atoms including the l7?-diol Iii-tetrahydropyranyl ether l7-acetate, respective anhydride and acid halides of lower alkanoic acids such ly. After the isolation of these derivatives (i.e. after the as acetic acid, propionic acid, t-butyric acid, valeric acid, addition of water to the reaction medium and ?ltration or and of aryl carboxylic acids such as benzoic and toluic extraction thereof) the addition of acetic acid or hydro 20 chloric acid to the derivative in aqueous alcohol will re acids, and the like. When an alkanoic acid derivative hav move the tetrahydropyranyl group and there is obtained ing up to 4 carbon atoms is desired, an acid anhydride the free hydroxylated derivative, e.g. l7 a-ethinyl estradiol is the acylating agent of choice. The concomitant alkynation and esteri?cation is com l7-acetate and 5-androstene-3;9,l7?-diol l7-acetate, re pleted within a very short time, the alkynation usually spectively. being completed within approximately a half-hour when 25 Hydroxyl functions in the 17-keto-androstane and 17 the solvent is a disubstituted alkanoic acid amide and keto-estrane starting steroids which are not protected prior within about three hours when tetrahydrofuran is used to alkynation and esteri?cation at C-l7, are transformed as solvent. After addition of the acylating agent to the to their lower alkanoate ester derivatives under the con ditions of my process. Thus, treatment of estrone and 5 alkynated reaction mixture in situ, only a short reaction 30 androsten-35-ol-17-one with sodium acetylide in dimethyl time is usually required (and sometimes but a minute or formamide followed by acetic anhydride, and isolation of two) prior to pouring the reaction mixture into Water the thereby formed l7u-ethinyl-l75-acetoxy derivatives by and isolating the resulting product. the addition of water followed by extraction and recrystal My process ?nds its greatest usefulness in the prepara lization will yield l7a-ethinyl estradiol diacetate and 17a tion of 17a-alkynyl-l7n-alkanoyloxy derivatives of ster ethinyl-5-androstene-3{3,l7?-diol diacetate, respectively. oids containing acid sensitive function, such as described When preparing 17a-alkynyl-17?-alkanoyloxy estranes hereinabove. In general, however, any l7-keto steroid of and androstanes containing other esteri?ed hydroxyl the androstane and estrane series may be subjected to the groups, the quantity of alkanoic acid anhydride which is action of an alkyn-at-ing agent followed by the in situ to ‘be added in situ should be increased by about one mole addition of a lower alkanoic anhydride or halide and there 40 for each free hydroxyl group to ensure complete esteri?ca will be formed a l7a-alkynyl-l7?-lower alkanoyloxy ster tion of the resulting product. The esters of primary and oid of the androstane and estrane series. secondary alcohols in the l7a-alkynyl-17B-acyloxy deriva Included among the 17-keto estranes useful as starting tives thus prepared may be converted to the corresponding compounds are 3 - methoxy - 2,5(10) - estradien-l7-0ne, free hydroxyl functions by preferential hydrolysis accord estrone, and methyl analogs of estrone such as 1,2-di ing to procedures known in the art. Thus l7a-ethinyl methylestrone, 2—methylestrone, lé?-methylestrone, 6B estradiol diacetate and 17a-ethinyl-5androstene-35,175 methylestrone; unsaturated analogs thereof such as 6 dehydroestrone, 1-methyl-6-dehydroestrone, 1,2-dimethyl diol diacetate upon treatment with a half-molar quantity 6-dehydroestrone, 6-methyl-6-dehydroestrone, 7-dehydr0 of sodium carbonate in aqueous methanol yields 17a estrone (equilin), 6,8-bis-dehydroestrone (equilenin); hy ethinylestradiol 17-ac'etate and 17a-ethinyl-5-androstene 50 35,17?-diol 17-acetate, respectively. droxylated derivatives and ethers thereof such as 65 When the hydroxyl functions in the starting 17-keto methyl - 7a - hydroxyestrone, llB-hydroxyestrone, l-me androstane or l7-keto estrane are hindered secondary or thoxyestrone and Z-methoxyestrone. tertiary and, in carrying out my process, there is employed Some 17-keto androstanes useful as starting compounds , .a molar quantity of acylating agent approximately equiva are S-androsten-S?-ol-l7-one, 4-androstene-3,ll,l7-trione, lent to that of alkylating agent, there is obtained a 1711 16B-methyl-19-nor-4-androstene-3,17-dione, 4-androstene alkynyl-l7?-acyloxy-androstane or estrane possessing un 3,17-dione, 4-androsten-35-ol - l7 - one, l9-nor-4-andro esteri?ed secondary or tertiary vhydroxyl functions. Thus, stene-3,l7-dione, 5-androsten-3u-ol-l7-one, 1,4,6-andro androstan-llB-ol-l7-one, upon reaction with about three statriene-3,l1,17-trione, S-androstene-Mj? - diol-17-one, moles of sodium acetylide followed by treatment with 6-fluoro (a and B)-4-androsten-l7-one, 19-nor-4-andro~ 60 about three moles of acetic anhydride will yield 170: stene-ll,l7-dione, 4 - androstene - 11,17 - dione, llB-hy ethinylandrostane-l15,17B-diol 17 -acetate. droxyandrostan-l7-one, 1,4-androst-adiene-3,l7-dione. Starting compounds possessing a A4-3-keto moiety, e.g. When it is desired that an ether derivative be present in l9-nor-4-androstene-3,l7-dione and 6a-?uoro-4-androsten a l7u-a1kynyl-17?-lower alkanoyloxy androstane or es 3,17-dione, are preferably converted to the corresponding trane prepared ‘by my process, the hydroxyl functions in 65 alkyl enol-ether derivative prior to alkynation and esteri? the l7-keto starting steroid, e.g. as in estrone (3-hydroxy cation in order to obtain the coresponding l7a-alkynyl 1,3,5(l0)-estratrien-17-one) are preferably converted to their ether derivatives (e.g. estrone methyl ether) prior to 17?-lower alkanoyloxy-4-androsten-3-one. Thus, 19-nor-4 reaction with sodium acetylide in dimethylformamide fol androstene - 3,17 - dione 311(1‘600 - ?uoro - 4 - androsten - 3, lowed by acetic anhydride (for example) to obtain the cor l7-dione, upon treatment with ethyl orthoformate in responding 17a-alkynyl-17B-lower alkanoyloxy derivative dioxane in the presence of acid, accordng to known pro thereof, e.g. 17 a-ethinylestradiol 3-methyl ether 17 acetate. cedures, are each converted to the corresponding ethyl When preparing l7a-alkynyl-17B-1ower alkanoyloxy enol-ether intermediate, i.e. 3-ethoxy-l9-nor-3,S-andro estranes and androstanes having free hydroxyl functions, stadien-l7-one and 3-ethoxy-6-?uoro~3,5-androstadien-l7 the hydroxylated 17-keto starting steroids of the estrane one, respectively, which, upon reaction with sodium. and androstane series are conveniently converted to their 3,409,643 acetylide in dimethylformamide followed by the in situ 6 addition of acetic anhydride, yields 3-ethoxy-17a~ethinyl~ tion the resulting precipitate comprising 3-methoxy-l7a 19-nor-3,5-androstadien-l713-01 17-acetate and 3-ethoxy-6 ethinyl-2,5 ( 10)-estradien-17}8-ol 17-acetate. ?uoro-3,5-androstadien-17,8-01 17-acetate, respectively. crystallization under an ' Treatment of the foregoing with dilute hydrochloric acid aqueous methanol containing a drop of pyridine. M.P. in aqueous methanol regenerates the 3-keto-A4-system and 163-170° C. [a]D+58.8° . there is formed 17a-ethinyl-19-nor-4-androsten-1718-01-3 In the above procedure, acetyl chloride may be sub one l7-acetate (17u-ethinyl-19-nor-testosterone 17-ace stituted for acetic anhydride, and there is obtained 3 tate—the known progestational agent, N orlutate) and 6a ?uoro-l7a-ethinyl-4-androsten-17 -ol-3-one 17-acetate. In order to prepare 17u-alkynyl-17/3-lower alkanoyloxy 10 androstanes having a 3-keto-AL4- system from the corre sponding 3,17-diketo~A1'4- androstane by my process, it is alkanoate ester, i.e. 3-methoxy-17a-ethinyl-2,5(lO)-es tradien-l7?-ol 17-propionate and 3-methoxy-17a-ethiny1 15 2,5 ( 10)-estradien-l7?-ol l7-n-butyrate, respectively. (B) To a solution of 0.5 g. of 3-methoxy-2,5 ( 10)-es tradien-17-one in 5 ml. of tetrahydrofuran, add 5 ml. of one l7-acetate. a mixture comprising 18 percent sodium acetylide in In general, Without effecting the course of my process xylene. Stir under nitrogen at 25° C. for four hours. Add (i.e. the concomitant formation of a 17a-alkynyl-l7/3 20 1.6 ml. of acetic ' ' alkanoyloxy steroid from a 17-keto precursor), the start ' mixture into ice water, ing l7-keto-androstanes and l7-keto-estranes may have the xylene. Collect by double bonds present in the steroidal nucleus such as at ?ltration the resulting precipitate comprising 3-methoxy C—1 and C-4 (subject to special treatment as described 17a-ethiny]-2,5(10)-estradien-l7?~ol 17-acetate by ?ltra hereinabove), at C-6, C-7, C-8, C—9(1l) and C-ll; 25 tion. Purify by crystallization from methanol containing methyl and hydroxy substituents and derivatives thereof a drop of pyridine. ' (e.g. esters and ethers) such as at C-4, C—6, C-7, and (C) In a manner similar to that described in procedure -11; ?uoro, as at C—6; and keto groups such as at C-3 1A, treat 3-ethoxy-2,5(10)-estradien-17-one with sodium (in a A‘*- and A1-4- A-ring) and at C-ll. Unprotected keto ' by acetic anhydride. Isolate and purify groups present other than at C-3 and/ or C-ll will under 30 product in the described manner-to give 3 go competing alkynation reactions to form the correspond ethoxy-l7u-ethinyl-2,5(10)-estradien-17,8-01 17-acetate. ing alkynated derivatives. Thus, androsane-3,l7-dione ' acetylide in dimethylform Example 2.—17a-ethinyI-4-estren-17,3-01-3-0ne 17-acetate addition of acetic anhydride ( 17a-ethinyl-19~nor-testosterone 17ace'tate) Will yield 3,17-bis-ethinyl-androstame-3,l7,B-diol diacetate. 35 When preparing a 9a-halogeno~1l?-hydroxy-Ih-ah (A) Dissolve l g. of 3-methoxy-17a-ethinyl-2,5(10) estradien-l7?-ol 17~acetate in 180 ml. of methanol and kynyl-l7,8-alkanoyloxy-androstane or estrane, the sub~ 20 ml. of water. stituents at C-17 are preferably introduced prior to those chloric acid, heat at C-9 and C—l1. Thus, 4,9(11)-androstadiene-3,17-dione after conversion to the corresponding 3-ethyl-enol-ether 40 followed by treatment of the 3-ethoxy-3,5,9(l1)-andro statrien-17-one thereby formed ' ' into Water and collect by ?ltration the resulting precipitate dimethylformamide and the in situ addition of acetic an comprising l7a-ethinyl-4-estren-17B-ol-3-one 17-acetate. ‘_ hydride, yields 3-ethoxy-17a-ethinyl-3,5,9(l1)-androsta In a similar manner, treat each of 3-methoxy-176r trien-l7/8-ol 17-acetate convertible by treatment with acid ethinyl-2,5(10)-estradien-l7?-ol l7-propi0nate ‘ and 3 to l7a-ethinyl-4,9( l 1)-androstadien-17/3-ol 17-acetate. methoxy-17a-ethinyl-2,5(l0) - estradien-17?-ol 17-n-bu Treatment of the ‘foregoing with hypobromous acid ac tyrate With hydrochloric acid in methanol. Isolate the re ' manner described above to obtain, respectively, l7a-ethinyl-4-estren- 1 7/3-01-3 -one ‘ l7-propion 50 ate and 17a-ethinyl-4-estren-3-one 17-n-butyrate. Alternatively, the compound of this example may be the corresponding 9u-chloro-11?-hydroxy and 9a-?uoro prepared as described below in procedures 2B and 2C. ll?-hydroxy derivatives of 17a-ethinyl-4-androsten-l7,8 (B) 170: ~ ethinyl - 5(10) - estren - 17,6 - ol - 3 - one ol 17-acetate, i.e. 9u-chloro-ll/i-hydroxy-l7a-ethinyl-tes 17-acetate.—Suspend 19 g. of 3-methoxy-l7a-ethinyl-2, tosterone 17-acetate and 9a-?uoro-11,8-hydroxy-17a-eth 55 5(l0)-estradiene-l7/3-0l 17-acetate in 1634 ml. of meth inyl-testosterone 17-acetate, respectively. For purposes of illustration, the process of this inven tion is disclosed in detail below. It is to be understood

60 vious equivalents will be apparent ol-3-oneing precipitate 17-acetate. comprising 17a-ethinyl-5(l0)-estren-l7B and the invention is to be limited claims. (C) l7u-ethinyl-4-estren- l 7l9-ol-3-one To a solution of l g. of 17a-ethinyl-5(l0)-estren-l7/3 Example 1.—35methoxy-17a-ethinyl-2,5( l0)-estradien ol-3-one l7-acetate in 180 ml. of methanol 1713-01 l7-acetate (A) To a solution of 40 g. of 3-methoxy-2,5(l0) estradien-l7-one in 800 ml. of dimethylforma-mide under into water and collect by ?ltration the resulting precipi tate comprising 17a-ethinyl-4-estren-l7,3-ol-3-one 17-ace .70 tate. ‘ I In a similar manner to that described in procedures B and C above, treat each of 3-methoxy-l7a-ethinyl-2,5~ (l0)-estradien-l7/3-ol l7-propionate ‘and 3-methoxy-l7a 75 ethinyl-2,5(10)-estradien-17/9-ol 17-n-butyrate in metha nol with oxalic acid, and isolate the resultant respective 3,409,643 S 3-methoxy-65-rnethyl-1,3 ,5 (10)-estratrien-l7-one, products ‘comprising l7a-ethinyl-5(10)-estren-175-ol-3 3-methoxy-6-methyl-l,3 ,5 ( 1O ) ,6-estratetraen-l7-one, one 17-propionate and 17a-ethinyl-5(10)-estren-175-ol-3 3-methoxy-1,3 ,5 ( 10) ,9 ( l 1 ) -estratetraen-17-one, one' l7-n-‘butyrate. Treatment of each of the foregoing 3-methoxy-1,3,5 (l0) ,6,8-estrapentaen-17-one, and esters with methanolic hydrochloric acid according to 3-methoxy-l,3 ,5 ( l0) ,7-estratetraen-l7-one. Procedure 2C yields respectively 17a-ethinyl-4-estren-175 Isolate the respective resultant products in a manner ol-3-one 17-propionate and l7a-ethinyl-4-estren-175-01-3 similar to that described in Example 1 to obtain o'ne '17-n-butyrate. l-methyl-3-methoxy-17a-ethinyl-1,3 ,5 ( 10 ) -estratrier1 _ Example 3.-—lO-hydroperoxy-17u-ethinyl-4-estren-l75 17 5-01 17-acetate, . ol-3-one 17-acetate 10 2-methyl-3 -methoxy-17 Ot-GthlIlYl-l ,3 ,5 ( l 0 ) -estratrien ‘Dissolve 13 g. of 17a-ethinyl-5(10)-estren-175-ol-3-one 175-cl 17-acetate, l-7-acetate?(the compound of Example 2B) in 200 ml. of 1,2-dimethyl-3 -methoxy- 17a-ethinyl-1 ,3 ,5 ( 10 ) -estratrien carbon tetrachloride. Pass oxygen through the solution - 17 5-01 17-acetate, while illuminating the solution with four ?uorescent lights V 1,2-dirnethyl-3 -rnethoxy-l7a-ethinyl-1,3 ,5 ( l 0) ,6-estra (four watts each)’. A precipitate slowly forms. Collect the 15 tetraen-175-ol l7-acetate, resultant precipitate after 20,30 and 95 hours. Chromato 1-methyl-3-methoxy-17a-ethinyl-1,3 ,5 (l0) ,G-estratetraen graph the combined precipitate over 400 g. of silica gel 175-o1 17-acetate, eluting with increasing percentages of ethyl acetate in 2,3-di-methoxy-17ot-ethinyl-1,3,5 ( 10)-estratrien-17 5-01 chloroform. Combine the like fractions as determined by > 17-acetate, thin layer chromatography and by infrared and ultra 20 3-methoxy-l65-methyl-17ot-ethinyl-l,3 ,5 (10)-estratrien violet‘ spectra data. Evaporate the combined fraction in 175-o1 17-acetate, vacuo to a residue comprising l0-hydroperoxy-l7tat-ethin 3 -methoxy-17ot-ethinyl-1,3 ,5 (10) ,6-estratetraen-175-ol - yl-4-estren-175-ol-3-one l7-acetate. Purify by crystalliza l7-acetate, tion from aqueous methanol. M.P. 178-180° C. [ab-29° 3-methoxy-65-methyl-17u-ethinyl-1,3 ,5 ( 10) -estr.atrien 25 17 5-01 17-acetate, (dioxane).Similarly, in the above procedure by substituting 17a 3-methoxy-6-methyl-l7wethinyl-l,3,5(10),6-estratetraen ethinyl-S(10)-estren-175-ol-3-one 17-acetate the corre 175-o1 l7-acetate, sponding l7-propionate and n-butyrate ester thereof, there 3 -methoxy-17-ethinyl-l,3 ,5 ( l0) ,9 ( l l ) -estratetraen is obtained lO-hydroperoxy-l7a-ethinyl-4-estren-175-ol 175-o1 17-acetate, 3-one l7-propionate and lO-hydroperoxy-l7a-ethinyl-4 30 3-methoxy-17a-ethinyl-1,3 ,5 ( l0) ,6,8-estrapentaen-175 vestren-175-ol-3-one 17-n-butyrate, respectively. ol l7-acetate, and 0 ‘Example 4.——10-hydroperoxy-17a-ethinyl-4-estrene-35, 3-methoxy-17u-ethinyl-1,3,5(10),7-estratetraen-175-ol 175-diol 17-acetate and the 3a-epimer thereof l7-acetate. In the above procedure, if there is used an anhydride To a solution of 50 mg. of 10-hydroperoxy-17 tx-ethinyl of other lower alkanoic acids such as propionic anhydride 4-estren-175-ol-3-one l7-acetate in 105 ml. of methanol and-caproic anhydride, there is obtained the correspond at room temperature, add 10 mg. of sodium borohydride ing 17-alkanoate acids, i.e., the 17-propionate and 17 in 10 ml. of methanol. Stir at room temperature for 90 caproate, respectively, of each of the above listed com minutes, then cautiously add glacial acetic acid dropwise until the reaction mixture is about pH 7. Concentrate the 410 pounds. reaction mixture in vacuo to a residue comprising 10 Example 6.-17ot-ethinyl-4-androsten-175-01-3 -one ;hydroperoxy - 17a - ethinyl - 4 - estrene - 35,175 - diol l7-acetate _17-acetate and the 3a-hydroperoxy epimer thereof. (A) 3-ethoxy - 17o: - ethinyl - 3,5 - androstadien-175 Purify by dissolving the residue in ethyl acetate, wash 01 17 - acetate.—-The requisite starting material, i.e., 3 ing the organic layer successively with dilute sodium bi ethoxy - 3,5 - androstadien - l7 - one is prepared accord carbonate, then water. Evaporate the ethyl acetate solu ing to known procedures via the action of ethyl ortho tion to a residue, then crystallize the residue from chloro formate on 4 - androstene - 3.17 - dione in dioxane in form to give lO-hydroperoxy-17u-ethinyl-4-estrene-35, the presence of ethanol and a strong acid such as sulfuric acid or p-toluene sulfonic acid. 175-diolTo obtain l7-acetate. the 3a-epimer thereof, evaporate the chloro To a solution of 2 g. of 3 - ethoxy - 3,5 - androstadien form ?ltrate containing 10-hydroperoxy-l7ot-ethinyl-4 l7-one in 40 ml. of dimethylformamide under an atmos estrene-3,17-diol 17-acetate and crystallize the resultant phere of nitrogen, add 0.69 g. of sodium acetylide. Stir precipitate withacetone-hexane to obtain 10-hydroperoxy at room temperature for 20 minutes, then add 1.1 ml. of 17a-ethinyl-4-estrene-3u,l75-diol 17-acetate. acetic anhydride. Stir at room temperature for two minutes, then pour into 400 ml. of water containing 12 ‘Example '5.-—3-methoxy-17a-ethinyl-1,3,5 ( 10) -estratrien g. of sodium chloride. Filter the resulting precipitate 175-o1 17-acetate ‘and analogs thereof comprising 3 - ethoxy - 17a - ethinyl - 3,5 - androstadien In a manner similar to that described in Example 1, 175-01 17-acetate. Purify by crystallization from methanol treat 3-methoxy-l,3,5(10)-estratrien-17-one (estrone containing a drop of pyridine. methyl ether) in dimethylformarnide under an atmosphere 60 In the above procedure, if propionic anhydride is sub of nitrogen with sodium acetylide followed by acetic an stituted for acetic anhydride, there is obtained 3 - ethoxy hydride. Isolate the resultant product in a manner similar l7u-ethinyl-3,S-androstadien-175-o1 17-propionate. to that described in Example 1 to obtain 3-methoxy-l7u (B) ?at-ethinyl - 4 -' androsten - 175 - ol - 3 - one 17 ethinyl-1,3,5 (10)-estratrien-l75-ol 17 -acetate. acetate (17a - ethinyl-testosterone acetate).—-Add 1 g. of In a similar manner, treat each of the following with 65 3-ethoxy - 17a - ethinyl - 3,5 - androstadien - 175 - ol sodium acetylide in dirnethylformamide followed by acetic 17-acetate to a solution comprising 190 ml. of methanol, anhydride in the above described manner. 20 ml. of water, and 1.27 ml. of concentrated hydro 1-methyl-3-rnethoxy-l,3,5 (10)-estratrien-17-one, chloric acid under an atmosphere of nitrogen. Allow this 2-methyl-3 -methoxy-1 ,3 ,5 ( 10 ) -estratrien-17-one, reaction mixture to stand under nitrogen at room tem _-1_ ,2-dimethyl-3 -methoxy-1,3 ,5 (10)-estratrien-17-one, 70 perature for three hours, then pour into Water. Filter the ,1,2-dirnethyl-3-methoxy-1,3,5 (10),6-estratetraen-17-one, _ resulting precipitate comprising 170: - ethinyl - 4 - andro .1-methyl-3-methoxy-L3 ,5 ( 10) ,6-estratetraen-17-one, sten - 175 - ol - 3 - one l7-acetate. Purify by crystalliza tion from acetone-hexane. 2,3-di-methoxy-1,3,5 (10)-estratrien-17-one, In a similar manner, treat 3 - ethoxy - 17a - ethinyl 3-methoxy-l65-methyl-1,3 ,5 ( 10)-estratrien-l7-one, -r Ur 3-methoxy-1,3 ,5 ( l0) ,6-estratetraen-17-one, 3,409,643 - 01 17 - propionate with an 1 aqueous methanolic hydrochloric acid solution. Isolate the l-methyl-I7a-ethinyl-1,3,5(10)-estratriene-3,1713-diol17a-ethinyl-1,3,5( 10)-estratriene-3,17?-diol diacetate, ethinyl-4-androsten-17/8-ol-3-one 17-propionate. diacetate, ' (C) In a manner similar to that described in Example 1,2-dimethyl-l7a-ethinyl-1,3,5( 10)-estratriene-3,17,8-diol treat each of the following with ethyl orthoformate Cl diacetate, in dioxane in the presence of ethanol and 1,2-dimethyl- l 7a-ethinyl- 1,3,5 ( l0) ,6-estratetraen-3, 1 7B fonic acid: 19 -. nor - 4 - androstene - 3,17 - drone, 1613 diol diacetate, methyl - 19 - nor - 4 - androstene - 3,17 - dione, 4-andro 1-methyl-17u-ethinyl-L3 ,5 ( 10) ,6-estratetraen‘3, 1 7,8 stene - 3,11,17 - trione, and 19 - nor - 4 - androsten- 10 diol diacetate, 3,11,17 - trione, and there is obtained their respective ethoxy enol ethers, namely, l7a-ethinyl-1,3,5(10),6-estratetraene-3,l7/9-diol diacetate, 6l3-methyl-ldiacetate, 7a-ethinyl- l ,3 ,5 ( 1 0) -estratriene-3, 17/3-d1'ol 3-ethoxy-19-nor-3,5-androstadien-17-one, 6-methyl-l7a-ethinyl-1,3,5( 10),6-estratetraene-3,1713 3-ethoxy-3,S-androstadiene-11,17-dione,3-ethoxy-16B-methyl-l9-nor-3,5-androstadien-17-one, and 15 diol diacetate, 3-ethoxy-19-nor-3 ,5 ~androstadiene-1 1, 1 7-dione. 17a-ethinyl-1,3,5(10),6,8-estrapentaene-3,l713-dioldiacetate, In a manner similar to that described in the second 17a-ethinyl-1,3, ( l O),7-estratetraene-3, l 7/3-diol diacetate, paragraph of Example 6A, treat each of the foregomg and ethoxy enol ethers with sodium acetylrde 1n dlrnethyl- 20 formamlde under nitrogen followed by acetic anhydrrde 6?-methyl-17a-ethinyl-1,3,5(10)-estratriene-3,7u,17/3-trioltriacetate. Isolate the respective resultant products in a manner slmr lar to that described to obtain

3-ethoxy-17a-ethinyl-19-nor-3,S-androstadien-U?-ol17-acetate, 25 3-ethoxy-16?-methyl-17a-ethinyl-19-nor-3,5-androstadien175-01 l7-acetate, . 'butyratenamely theesters, di- respectively.(or tri-) propionate, and the di- (or tri-) 3-ethoxy-17a-ethinyl-3,5-androstadiene-17?-ol~1l-one17-acetate, and Example 8.—17a-ethinyl-5-androstene-313,17,8-diol l7-acetate 3-ethoxy-17u-ethinyl-19-nor-3,5-androstadien-l713-01ll-one 17-acetate. (A) 5-androsten-3?-ol - 17 - one 3 - tetrahydropyroanyl In a manner similar to that described in Example 6B, ether.—-To a mixture of 1. g. of 5-andr0sten-3/3-0l-l7-one treat each of the foregoing 3 - ethoxy - 17a - ethinyl~ in 50 ml. of ether and l g. of 2,3 dihydropyran, add four 3,5 - androstadienes with aqueous methanolic hydrochloric 35 drops of a prepared solution of p-toluene sulfonic acid acid, and isolate the resultant product in a manner similar (1 g.) in 100 ml. of ether. Allow the reaction mixture to to that described to obtain, respectively, stand at room temperature for four days, then add an ad 17a-ethinyl~19-nor-4-androsten-17?-ol-3-one 17-acetate (i.e., 17a-ethinyl-19-nor-testosterone l7-acetate), 16?-methyl-17a-ethinyl-19-nor-4-androsten-17?-ol-3-0ne 40 17-acetate, . 17u-ethinyl-4-androsten-1719-01-3,l l-dione 17-acetate, and 1 7a-ethinyl-l9-nor-4-androsten-1 7,3-01-3, l l-dione 17 acetate. Example 7.—-l7a-ethinyl-17/3-acetoxy derivatives of hy- 45 sten-3?-ol-17-one-3~tetrahydropyranyl ether, which is used droxylated androstanes and estranes following.without further purl?cation in procedure 8B immediately Treat 40 g. of each of the following with dimethyl (B) l7oc-ethinyl-5-androstone-3,3,l7B-diol 3-tetrahydro formamide under an atmosphere of argon with sodlum pyranyl ether 17-acetate.—To a solution of 1 acetyltde 1n the manner described in Example 1A fol- 5O drost'en-3?-ol-17-one 3-tetrahydropyranyl ether ru 30 ml. lowed by treatment with acetic anhydrlde the quantity of acetic anhydride being approximately twice that used in Example 1 (i.e. around 39 ml. . 5-androsten-3?-ol-17-one, Stir at room temperature ?ve minutes, then pour, into a 4-androsten-3l3-ol~l7-one, 55 saturated aqueous solution of SOdlUIIl chloride. Collect by 5-androsten-3a-ol-l7-one, ?ltration the resulting precipitate comprising 17a-ethinyl 5-androstene-la,3/3»diol-17-one, 5-androstene-3B,l7/3-diol 3-tetrahydropyranyl l7-acetate. 1,3,5 ( 1 0)-estratrien~3-ol-l7-one, (C) 17u-ethinyl-5-androstene-3,8,17B-diol 17-acetate.~ l-methyl-1,3,5(10)-estratrien~3-ol-17-one, Dissolve 0.2 g. of 17a-ethinyl-5-androstene-3B,17?-diol 1,2-dimethyl-1,3,5 ( 10)-estratrien-3-0l-l 7-one, 60 3-tetrahydropyranyl ether 17-acetate in 40 ml. of ethanol, 1,2-dimethyl-1,3,5 ( 10) ,6~estratetraen-3-ol-l7-one, 1~methyl-1,3,5 ( 10),6-estratetraen-3-ol-17-one, 1,3,5 ( 1 0) ,G-estratetraen-S-ol-l 7-one, 6;3-methyl-1,3,5 ( 10)-estratrien-3-ol-l7-one, cipitate comprising 170: - ethinyl-5-androstene-3/8,17/3-di0l 6-methyl-1,3,5 ( 10),6-estratetraen-3-ol-17-one, 65 17-acetate. Purify by crystallization from acetate-hexane. 1,3,5 ( l0) ,6,8-estrapentaen~3-ol-17-0ne, Alternatively, this example is prepared 1,3,5 ( 10),7-estratetraen-3-ol-l7-One, and in the followin manner: To 3 g. of 17u-ethinyl-5-andro~ 6?-methyl-1,3,5 ( 10)~estratriene-3, 7a-diol~17-one. stene-3,8,17?-diol diacetate (prepared as described in Ex ample 7), add 0.5 g. of carbonate in 100 ml. of Isolate the respective resultant products in a manner similar to that described in Example 1A to obtain 70 methanol-water (9:1). Allow the reaction to stand at 17a-ethinyl~5-androstene-35,17,8-diol diacetate, 17a-ethinyl-4-androstene-3B,17?-diol diacetate, precipitate com 17a-ethinyl-5-androstene-3a,17,8-di0l diacetate, prising 17a-ethinyl-5~androstene-3,B,l7?-diol 17 - acetate. l7a-ethinyl-5-androstene-1a,3?,17?-triol triacetate, 75 Purify 'by crystallization from acetone-hexane. (D) In a manner similar to that described in procedure 3,409,643 v , 12 , > . . precipitate comprising"'l7og-ethinyhandrostane - 1118,173 8A, treat each of 5-androsten-3a-0l-l7-ohe, and 4'-an'dro diol l7=acetatexii " "v ‘ I ') ‘i " sten-3?-ol-l7-one with 2,3-dihydropyran in ether in‘the . Example l2;:3-methoxy<17a-propynyl-2,5 (10) -estra presence of p-toluene sulfonic acid to obtain, respectively, 5-andr0sten-3u-0l-l7-0ne 3-tetrahydropyranyl ether and 4-androsten-3?-ol-l7-one 3-tetrahydropyranyl ether. In the 1To1'a solution‘ of 0;4*g.' of'3-m'ethoxy-2,5 (‘10)‘estradien manner described in procedure 8B, treat‘ each ofv the l7"-one in ‘8.5 m1: ofdimethylformamide under an’ atmos foregoing t'etrahydropyr'anyl ethers with sodium acetylide phere-of nitrogen, add (){1‘36 g.~-o'f~a sodium salt of methyl acetylene (i.e. the sodium salt of'propyne) dispersed in in dimethylformamide followed by acetic anhydride to ob. xylene ‘(prepared according t‘o'known' procedures by tain,tetrahydropyranyl respectively, ether l7-acetate, and 17a-ethinyl-4-an placing propyne into a solution of liquid ‘ammonia and drostene-3 5,1718-diol 3-tetrahydropyranyl ether ‘ l7-acetate. sodium, and then displacingthevammonia with xylene). Stir atroomternperaturhe. for 20 minutes, then add,0.21 Treat each of the foregoing l7a-ethinyl androstene 3-di Stir the reaction mixture vfor ?ve hydropyranyl ether derivatives with aqueous ethanolic hy ' 1. ml. of acetic anhydride. drochloric acid in the ‘manner described in Example 80 minutes at room temperature, then pour-the reaction mix to obtain, respectively, l7u-ethinyl-5-androstene-3a,l7? ture, into an aqueous saturated sodiumchloride solution. Extract the ‘mixture with methylene 'fchlorideia‘nd evapo diol l7-acetate, and 17a-ethinyl-4-androstene. 3B,17B'diol rate the combined methylene chlo‘ 'de‘ext'racts to‘a residue 17-acetate. . ' comprising IZa-iiietho'xy-1'7o£ipropyhyl-2,5 (l0) -’ festr'adierh Example 9.—-l7a-Ethinyl-1,3,5(10)-estratriene-3,l7;8-diol 1 175-01 _ l7-ac’et'ate. Purifyby crystallization'from ' aqueous 17-acetate (l7oc-e’thiny1 estradiol 17¢acetate) 20 ethanol containing “a” drop of‘pyridin’e. v f " In the above procedure, if in place of acetic anhydride (A) l,3,5(l0) - estratrien-3?-ol-l7-one 3 - tetrahydro there is used the anhydride of'other lower alkanoic acids, pyranyl ether'.-In a manner similar to that described such as propionic and n-butyric 'anhydride,-there is ob in Example 8A, treat 1,3,5 (l0)-estratrien-3-oI-l7-one ,1 tained the corresponding lower alkanoic acidester, i.e. 3' with 2,3-dihydropyranyl in' ether in the presence of p 25 methoxy-l7a-propynyl-2,5 ( l0) -estradien-l7 18-01 17-propi toluene sulfuric acid. Isolate the resultant’v product in a onate, and. 3-methoxy-l7a-propynyl-2,5(10) - estradien manner similar to that described to obtain 1,3,5 (10) estratrien-3-ol-17-one 3-tetrahydropyranyl ether. 1773-01 l7abutyrate, respectively. ' ‘ I claim: ‘. > » - v . - (B) l7u.-ethinyl-1,3,5(l0)-estratriene-3,l75-diol 3-tet- _ . 1. A process for preparing a l7a-alkynyl-l7f3-alka rahydroether 17-acetate.--In a manner similar to that 30 described in Example 8B, treat 1,3,5(l0)-estratrien-3-ol noyloxy. steroid of the androstane and estraneseries which 175-01 3-tetrahydropyranyl ether with sodium acetylide in comprises treating a l7-keto steroidv offthe .androstane and estrane series vwith an ‘alkali metal acetylideyadding in dimethylformamide followed ‘by treatment with acetic an? situ to the .,l7a-alkynyl¢l7?-hydroxy metal salt interme hydride. Isolate the resultant product in the manner simi diate thereby formedan acylating agentselected from lar to that described to obtain l7a-ethinyl-1,3,5 (10)-estra the group consisting of a lower alkanoyl anhydride and triene-3,l7l9-diol 3-dihydropyranyl ether l7-acetate. a lower alkanoyl halide; and'treating said metal salt in (C) l7a-ethinyl-1,3,5 (10)-estratriene-3,l75 - diol l7 acetate.-—In a manner similar to that described in Ex termediate with said acylating agent for less than an hour ample 8C, treat 17a-ethinyl-l,3,5(10)-estratriene-3,17B at temperatures up to 50° C. ' ' ' ‘ ' diol 3-tetrahydropyranyl ether 17-acetate‘ with aqueous 40 2. The process of claim 1 when carried out in an N,N disubstituted lower alkanoic acid amide. ' ethanolic hydrochloric acid. Isolate and purify there 3. The process of claim 1 when carried out in tetra sultant product in the described manner to obtain 17d ethiny1-1,3 ,5 ( l0) -estratriene-3, l7 ?-diol 17-aeetate. hydrofuran. , Alternatively, the compound of this example is pre 4. The process of claim lwherein said-alkali metal acetylide is sodium acetylide.- V. - . pared as follows: Treat 17a-ethinyl-1,3,5(10)-estratriene 45 ‘5. The process of claim 1 wherein said alkali metal 3,17?-diol diacetate (prepared as described in Example 7) with sodium carbonate in aqueous methanol in the acetylide is sodium acetylide andlwvherein said acylating agentis a lower alkanoic anhydride. _ " _ I manner described in the alternative procedure of Example 6. The process of claim 1 wherein said alkali metal 8C. Isolate and purify the resultant product in the de scribed manner to obtain 17a~ethinyl-1,3,5(10)-estratri acetylide'is sodium acetylide and wherein said acylating agent is a lower alkanoyl halide. ‘ p _ ' Vene-3,17?-diol 17-acetate. 7. The process of claim 1 when carried out in dimethyl Example 10.-6?-methyl-l 7a-ethinyl-l ,3,5 ( l0) -estratri formamide and wherein said alkalimetal acetylide is so‘ ene-3,7a, l7B-tri0l-17-acetate dium acetylide and wherein said acylating agent is a low To 1 g. of 6?-methyl-l7a-ethinyl-1,3,5(10)-estratriene 55 er 8.alkanoic The process anhydride. accordingto claim 7' wherein.V said. lower 3,7a,17;3-triol triacetate (prepared as described in Ex alkanoic anhydride is acetic anhydride. - ample 7), add 0.23 g. of sodium hydroxide dissolved in 9. A process ‘for preparing 3-alkoxy-17a-alkynyl-17,8 60 ml. of methanol-water (9:1). Allow the reaction mix alkanoyloxy-,2,5(l0)-estradiene;which comprises treating ture to stand at room temperature for two hours, then 3-alkoxy-2,5_ ('10)-estradien-17-one with an alkali metal add hydrochloric acid dropwise until the solution is about 60 acetylide; and: adding in situ .to- the l7a-alkynyl-l7B-hy pH 5. Extract the reaction mixture with chloroform. Com droxy metal salt intermediate thereby formed: an acylat bine the chloroform extracts and evaporate to a residue ing agent selectedfrom the group consisting. of a lower comprising \6B-methyl-17a-ethinyl-l,3,5(l0) - estratriene alkanoyl anhydride. and a lower alkanoyl halide. - 10. A process according to claim 9 when carried out 65 in dimethylforrnamide and wherein said 3-alkoxy-2,5 (l0) Example 11.--17a-ethinyl-androstane-l16,17?-diol l7 estradien-17-one is 3-methoxy-2,5(l0)-estradien-l7-one, ' acetate . said alkali metal acetylide is sodium acetylide, said acylat .To a solution of 2.9 g. of androstan-11?-ol-l7-one in ing agent is acetic anhydride, and wherein said 3-alkoxy atmosphere of . l7a-alkynyl-l7?-alkanoyloxy-2,5 ( loj-estradiene prepared 70 ml. of dimethylformamide under an 70 argon, add 0.48 g. of sodium acetylide. Stir at room tem is 3 - methoxy-17a-ethinyl-2,5(10)-estradien-l7p-o1 17 perature for 15 minutes, then add'rapidly 1.02 gpof acetate', ' . v . v . ' acetic anhydride. Stir at room temperature for one min said ~proces for preparing‘ 3-methoxy-l7a-ethinyl~2,5 ute, then pour into 500 ml. of water saturated with so (l0)-estradien--l7?-ol 17~acetate comprising treating dium chloride. Continue. stirring under an atmosphere of 3 - methoxy - 2,5(10)-estradien-l7-one with sodium argon for two hours, then collect by ?ltration the resultant 3,409, 643 acetylide in dimethylformamide; and adding acetic 14 anhydride in situ to the thereby formed 3,076,829 2/1963 Reimann et a1 . ____ 260—397.45 l7?-hydroxy sodium salt intermediate. 17a-ethinyl- 3,260,733 7/1966OTHER Foell REFERENCES et a1. ______260—397.3

UNITEDReferences STATES Cited PATENTS 5 reliedLowenthal, “1) Letrohedion 6, pp. 269-303 (1959) (p. 300 2,970,157 1/1961 Cutler et a1 ______3,072,646 1/1963 Fried et a1. 260—397.45 LEWIS GOTTS, Primary Examiner. 3,072,686 I/ 1963 Wettstein ______260-23955 et aL ____ 260_397_4 E. G. LOVE, Assistant Examiner.