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United States Patent Of?Ce 3,409,643 Patented Nov 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.
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