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United States Patent Office Patented Sept 3,470,217 United States Patent Office Patented Sept. 30, 1969 2 alkoxides may be mentioned: sodium methoxide, potas 3,470,217 sium methoxide, sodium ethoxide and potassium ethoxide. PROCESS FOR THE PREPARATION OF The hydrocarbon sulfoxide may be of any of the known ALKYNYL CARBNOLS Sulfoxides such as methylethylsulfoxide, diethylsulfoxide, Robert Ginsig, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of dimethylsulfoxide, etc. Again, on the basis of availability, Panama cost and reactivity, dimethylsulfoxide is presently pre No Drawing. Filed Apr. 7, 1966, Ser. No. 540,815 ferred. Int, C. C07 167/00 In practice, the acidic alkyne is first introduced into a U.S. C. 260-397.4 18 Claims Substantially nonaqueous, preferably anhydrous, mixture O of the alkali metal lower alkoxide and the hydrocarbon sulfoxide. While this initial medium may consist solely of ABSTRACT OF THE DISCLOSURE the alkoxide and sulfoxide, the latter thus serving as the Preparation of 17B-hydroxy-17 oz-ethynyl steroids, use solvent, it is often desirable to provide an additional ful as estrogenic and progestational agents, from the corre solvent component in the form of one or more inert, sponding 17-keto steroids by allowing the latter to react 5 organic liquids. For this purpose, any organic liquids with acetylene in the presence of an alkali metal alkoxide which are free from acidic hydrogen atoms may be used, and dialkylsulfoxide. the Selection depending in part on the solubilities and chemical reactivity of the present and future reactants. Among numerous such solvents are included: diethyl The present invention is directed at a novel process in ether, dioxane, tetrahydrofuran, diglyme, benzene, tolu organic chemistry. More particularly, the present inven ene, Xylene, and the like. tion concerns a valuable synthetic route for the prepara Thus, the mixture of the alkali metal alkoxide and the tion of carbinols. Specifically, this process pertains to an sulfoxide is first saturated with acidic alkyne. After allow inexpensive, convenient and improved route for the prep ing this mixture to equilibrate, the carbonyl compound is aration of alkynyl carbinols from aliphatic or alicyclic introduced. For ease of handling and homogenicity of the carbonyl derivatives. reaction mixture, the carbonyl derivative is ideally dis Among the commercially feasible processes for the solved in an inert organic solvent, generally the same preparation of alkynyl carbinols such as the hypnotics solvent as is used for a cosolvent as described above, if meparfynol (3-methylphentyn-3-ol) and ethchlorvynol such is employed. Often the reaction can be advanta (ethyl-6-chlorovinyl ethynyl carbinol), synthetic steroidal 30 geously executed without temperature adjustment, i.e., it hormones such as 17 oz-ethynylestr-4-en-17f8-ol-3-one, 17 oz is successful at a typical room temperature of about 25 C. ethynylestr-5 (10)-en-176-ol-3-one, and 3-methoxy-17a Should the reaction be overly vigorous or sluggish, as the ethynylestra-1,3,5 (10)-trien-17 3-ol, and various commer case may be, cooling or heating respectively may be cial chemical intermediates such as 3-methylbutyn-1-ol applied as appears necessary. 35 Alternatively in some applications, it is desirable to first used in the preparation of isoprene, is the alkynylation of place the carbonyl reactant in a mixture of the alkoxide aliphatic or alicyclic carbonyl compounds. Heretofore the and the sulfoxide and then introduce the alkyne. formation of a sufficiently anionic reaction specie of the For maximization of yields, it has been found desirable alkyne reactant has required utilization of an extremely to continue introduction of the alkyne during the reaction, strong base such as an alkali metal t-alkoxide, an alkali 40 metal amide, or even an alkali metal itself such as lithium thus providing an excess of this reagent. At initiation, or sodium often in a reaction medium such as liquid therefore, one should utilize an amount of alkali metal ammonia. In addition to the obvious cost and danger of lower alkoxide which is at least equimolar to the amount such reagents, such strong bases increase considerably of carbonyl derivative to be introduced, and preferably the possibility of undesired side reactions. an excess such as 2 to 10 molar equivalents. One highly The present invention is based on the discovery that 45 satisfactory ratio is about 5 molar equivalents of alkoxide under certain conditions, more fully defined hereafter, the for each molar unit of carbonyl derivative. formation of carbinols through the alkynylation of car Upon completion of the reaction, the period for which bonyl compounds may be successfully accomplished in will obviously depend on the particular reactants but the presence of basic materials which are less alkaline. 50 which generally is from 1 to 10 hours, e.g., 3 to 5 hours These materials are less dangerous to use, from the stand with a suitable rate of introduction of the acidic alkyne, point of both operator and undesired side reactions, and the reaction product is acidified prior to isolation. This less expensive than those previously in use. is readily accomplished, for example, by merely pouring According to the present invention, an aliphatic or ali the reaction medium into an aqueous Solution of acid, cyclic ketone is treated with the reaction product obtained 55 such as sulfuric, hydrochloric, acetic, or the like acid. from an alkali metal lower alkoxide, a hydrocarbon To overcome the heat of neutralization, this aqueous sulfoxide and from an acidic alkyne. By the term "acidic acid medium may also contain ice, or it may be cooled alkyne” is simply meant an acetylenic compound having a externally. The reaction solvent is then removed by con hydrogen atom bound to at least one of the carbon atoms ventional methods such as evaporation, physical separa bearing the triple bond, as for example acetylene or a tion, vacuum distillation, or the like. The reaction product monosubstituted acetylene derivative Such as methyl 60 is then collected, if insoluble, by filtration, centrifugation acetylene, ethylacetylene, or the like. or the like, or if soluble, by evaporation and concentra By the term “alkali metal alkoxide” is intended an ionic tion, solvent extraction or other equivalent conventional substance having as its cation an alkali metal ion, e.g., methods. Purification via the usual techniques, e.g., re sodium, potassium or lithium, and as its anion the de crystallization, distillation and the like may next follow, protonated residue of a hydrocarbon alcohol of from 1 or the reaction product may be utilized as such, depend to about 7 carbon atoms. While this alcohol moiety may ing upon the ultimate use of the particular material. contain from 1 to 7 carbon atoms, availability, cost and As but one example of the utility of this process, refer reactivity presently favor those primary and secondary ence may be made to the preparation of numerous valu alcohols of lower molecular weight such as methanol, able pharmaceuticals. For instance, ethynylated Steroids ethanol, propanol and isopropanol, particularly methanol 70 find wide use as estrogenic and progestational agents, and ethanol. Thus, as highly satisfactory alkali metal notable among these compounds being the 17 oz-ethynyl 3,470,217 3 and 17a-chloroethynyl derivatives of the androstane, the usual oxidative step in the overall synthetic route. In estrane and gonane series. Through utilization of the fore such cases, it is generally preferable to add the 19-hydroxy going process it is possible to readily ethynylate the compound or 19-aldehyde to a mixture of the alkali metal 17-keto group of various steroids in a more economical alkoxide, the sulfoxide and, if utilized, the solvent and and safer fashion than theretofore possible and to do so to add the alkyne to this mixture. Moreover, the final selectively even in the presence of other ketone groups acidification step of the present invention, in addition to which are less reactive. Thus, the present process permits producing the free 179-hydroxy-17a-ethynyl derivative, ethynylation of only the 17-keto group in steroids addi can also be used to simultaneously effect decarboxylation tionally possessing a keto group in conjugation with un of a 19-carboxylic acid derivative. Thus, upon introduc saturation, such as a 3,17-diketo-A-steroid or a 3,17 10 ing the reaction product of the alkynylation into aqueous diketo-Ai-steroid, a keto group with 3,y-unsaturation and acid, a 19-carboxylic acid group is eliminated. The crude a hydrogen atom on the ox-carbon atom, such as in a product is thus predominantly the 17a-ethynyl-17B 3,17-diketo-A5-steroid or a 3,17-A5(10)-steroid and/or a hydroxy-A5(10-19-norsteroid, which when also bearing a sterically hindered keto group such as in an 11,17-diketo 3-keto group may be converted to the corresponding steroid. 15 3-keto-17 oz-ethynyl-17 3-hydroxy-A-steroid through fur The starting steroid may contain a wide variety of ther acid treatment as described above. This acid treat other substituents elsewhere in the molecule, such as alkyl ment also insures complete decarboxylation. groups, halogen atoms, unsaturation, hydroxy groups, The following examples will serve to further typify the ether groups, and so forth. Of course, other keto groups nature of this invention, but as these are presented solely or aldehyde groups which are reactive, i.e., those which 20 for purposes of illustration, they should not be considered are not deactivated or sterically hindered, should be pro as a limitation on the scope or applicability of the inven tected as through the selective formation of ketals, semi tion. carbazones or other art recognized equivalent techniques. EXAMPLE 1. Among suitable steroidal starting materials are thus in Through a stirred suspension of 100 g.
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