3,274,182 United States Patent Office Patented Sept. 20, 1966

2 wherein R represents hydrogen or a tetrahydropyranyl 3,274,182 radical and R' represents hydrogen or a lower alkyl group PROCESS FOR REDUCING 19-METHYL-1,4-D EN-3- ONES TO CORRESPONDING 19-NOR-3-OXY-1,3, Such as methyl, ethyl, etc. 5(10)-TREENES Other steroidal 19-methyl-1,4-dien-3-ones advanta Hugh L. Dryden, Jr., Deerfield, and Gayle M. Webber, geously processed as described herein include 22a-spirosta Evanston, E., assignors to G. D. Searle & Co., Chicago, 1,4-dien - 3 - one, 20 - oxygenated pregna-1,4-dien-3-one l, a corporation of Delaware ketals of the formula No Drawing. Filled Dec. 24, 1964, Ser. No. 421,095 CHO Clains priority, application Canada, Dec. 28, 1963, 1 N 892,254 C Alk 20 Claims. (CI. 260-239.55) 10 H: S / This application is a continuation-in-part of our co pending application Serial No. 262,342 filed April 8, HC O 1959. This invention relates to a process for converting a 15 steroidal 19-methyl-1,4-dien-3-one to the corresponding 19-nor-3-oxy-1,3,5(10)-triene via alkali metal. In par ticular, this invention relates to new and improved means of converting a 17-oxygenated androsta-1,4-dien-3-one to wherein Alk is defined as before, as also the corresponding the corresponding 3-oxyestra-1,3,5(10)-triene whereby 20 20,20 - dialkyl ketals, and-indeed-substantially any the androsta-1,4-dien-3-one, in which ketonic oxygen steroidal 19-methyl-1,4-dien-3-one relatively impervious other than at 3 is preferably ketalized or comparably pro to prohibitive attack under the conditions of reaction tected, is contacted in an inert solvent medium by alkali set forth. metal or, more desirably, the radical anion deriving from The 3-oxyestra-1,3,5(10)-trienes produced by the process an adduct thereof with a polycyclic aromatic hydrocarbon 25 The 3 - oxyestra - 1,3,5 (10) - trienes produced by the such as biphenyl or naphthalene. A scavenger adapted process of this invention, upon simple acidification, afford to selectively react with the methyl alkali metal formed estra-1,3,5(10)-trien-3-ols of substantial commercial im in process tends further to improve the yield. portance, among which estrone is especially valuable at Typical of 17-oxygenated androsta - 1,4-dien - 3 - ones present because of its use as the starting material in a most advantageously converted to corresponding 3-oxy 30 wide variety of steroid syntheses. estra-1,3,5(10)-trienes by the disclosed process are an Most of the estrone on the market today appears to drosta-1,4-diene-3,17-dione 17 - ethylene, 17 - propylene, have been made by pyrolysis of androsta-1,4-diene-3,17 17-trimethylene, 17-(2,2'-dimethyl)trimethylene, and like dione. Perhaps because the most challenging aspect of ketals of the formula the pyrolysis is rupture of the 19-methyl carbon-carbon 35 bond, the involved process is not ordinarly regarded as Alk reductive; but the fact is that two hydrogen atoms have / N to be supplied in order for the pyrolysis to proceed, as O O shown below:

40 HC E3C g

EI 4N ol 45 CO -- CH wherein Alk represents an alkylene radical so disposed as to form a 5- or 6-membered ring with the attached The added hydrogens come from the mineral oil or oxygen and carbon atom number 17 in the steroid tetralin commonly used as a solvent for the pyrolysis. nucleus; androsta-1,4-diene-3,17-dione 17,17-dialkyl ketals And viewed in this light, such solvent can be considered such as the 17,17-dimethyl ketal; the isomeric 17-ketals as a reducing agent catalyzed by heat. which derive upon substitution of glycerol for the diol It might be assumed, therefore, that other, purely in Examples 40A, 41A, and 42A hereafter; and optionally chemical reducing agents would function alike to convert 17o - alkylated-176-hydroxyandrosta-1,4-dien-3-ones and steroidal 19-methyl-1,4-dien-3-ones to corresponding 19 their 17-ethers of the formula nor-3-oxy-1,3,5 (10)-trienes; but the prior art shows this not to be true. Thus, noble metal catalyst hydrogenation HC OR results in random reduction of the ring A unsaturations; s' "R" and another well-known chemical reducing system, alkali 60 or alkaline earth metal in liquid ammonia, serves merely to hydrogenate the A double bond Shapiro et al., Chem istry and Industry, 1962, 300 or, where lithium is the metal and the starting steroid 11-oxygenated, addition ally acetylate ring A if the 11-substituent is an acetoxy 65 group, and aromatize ring A with cleavage of ring B if 3,274,182 3 4. it is oxygen Tanabe et al., Tetrahedron Letters, No. 7, stances far exceed, the capacity of the metals themselves 601 (1961). to effect desired reductions in maximum yields of purest Alcoholic zinc has been found to convert Steroidal 19 products. Derivation of these radical anions can be methyl-1,4-dien-3-ones to corresponding 19-nor-3-oxy graphically represented thus 1,3,5 (10)-trienes provided a A6, A8, or A9(11) double bond 5 is present U.S. 3,040,036), and so too has zinc in an aqueous aromatic base such as pyridine, picoline, lutidine, collidine, quinoline, etc. U.S. 3,040,037. On the other C-C e hand, when the latter reagent was used to reduce andro ( > K); M = ( )-X). M. sta-1,4-diene-3,17-dione, the major (80%) reaction prod O uct was the so-called cryptophenol, 1-hydroxy-3-methyl estra-1,3,5(10)-trien-17-one, and only 4% estrone was isolable. Tsuda et al., J. Org. Chem., 26, 2614 (1961). Moreover, zinc dust and acetic acid produced no ring A aromatization whatsoever in androsta-1,4-diene-3,17-di 5 one, but instead afforded a substance assumed to be a bis (Or CO-CO compound showing polyene unsaturation. J. Org. Chenn., loc. cit.). etc., M being taken to represent the alkali metal. Illus It follows that the process here sought to be patented trative of polycyclic aromatic hydrocarbons other than is unforeshadowed by the prior art, and the high yields 20 biphenyl and naphthalene adapted to form Suitably ioniz of pure products which characterize preferred embodi ing adducts as disclosed herein are methylnaphthalene ments of the invention are entirely unexpected. (both isomers), dimethylnaphthalene (10 isomers), phen As indicated above, there is substantially no limit to anthrene, terphenyl (3 isomers), anthracene, acenaph the variety of steroids which can be used as starting ma thene, and fluoranthene. A few oxygen-containing poly terials in the subject process so long as they are 19 25 cyclic aromatic compounds likewise form such adducts methyl-1,4-dien-3-ones wherein no other function is sub for example, dibenzofuran and benzophenone. Among ject to undesirable reduction or would otherwise interfere these various substances, which are hereinafter termed With the contemplated reaction-for example, by being "radical anion precursors,' a sub-group consisting of bi unstable under the strongly alkaline conditions which pre phenyl, naphthalene, methylnaphthalene, phenanthrene, vail. In the case of androsta-1,4-diene-3,17-dione and 30 and terpheny is characterized by so superior a perform comparable polyones, ketalization of the potentially inter ance in the process of this invention as to dictate separate fering keto substituents serves admirably to protect against recognition. Thus, for example, when androsta-1,4-diene inimical side reactions, since the ketal group is notably 3,17-dione 17-ethylene ketal is reduced with lithium in stable to reduction and alkali. Moreover, it has the ad the presence of one of the latter, especially preferred vantage of being readily removed by acid hydrolysis. 35 radical anion precursors, using tetrahydrofuran as a Sol Those skilled in the art will of course appreciate that vent, the yields of estrone isolable upon acidification other chemical groups possessed of the indicated prop consistently range upward of 68% under optimum con erties likewise would afford the required protection. ditions, whereas other radical anion precursors (and, in Among the various alkali metals with which steroidal deed, alkali metals alone) in comparable operations af 19-methyl-1,4-dien-3-ones can be reduced to correspond 40 ford yields of estrone ranging downward from 1776. ing 19-nor-3-oxy-1,3,5 (10)-trienes as described herein, Of critical importance to the contemplated adduct for lithium has generally been the one of choice to date, mation is the solvent in which formation is undertaken. although sodium and potassium also are most effective in Notwithstanding, a wide range of preponderantly ethereal Selected instances, as are mixtures of these metals- for solvents suggest themselves for this particular purpose example, sodium and potassium alloy. Thus, when the 45 Cf. Scott et al., loc. cit.). These include lower aliphatic metal is used "directly' (which is to say in the absence ethers such as dimethyl ether, methyl ethyl ether, methyl of a polycyclic aromatic hydrocarbon such as biphenyl propyl ether, methyl isopropyl ether, and methylvinyl or naphthalene with which it forms an adduct), better ether; fully alkylated polyhydric alcohols such as ethylene yields of 19-nor-3-oxy-1,3,5 (10)-triene are often achieved glycol dimethyl ether, ethylene glycol methyl ethyl ether, with potassium or sodium and potassium alloy than with 50 ethylene glycol diethyl ether, ethylene glycol methylbutyl lithium or sodium alone, possibly because the former are ether, ethylene glycol ethylbutyl ether, ethylene glycol di liquids at usual operating temperatures in preferred sol butyl ether, diethylene glycol dimethyl ether, diethylene vents such as tetrahydrofuran, and so make better contact glycol methyl ethyl ether, triethylene glycol dimethyl ether, with the steroid to be reduced. The high melting points tetraethylene glycol dimethyl ether, propylene glycol di of lithium and sodium militate against their being molten 55 methyl ether, dipropylene glycol dimethyl ether, glycerol in most organic Solvents at less than supra-reflux tem trimethyl ether, glycerol dimethyl ethyl ether; acetals such peratures. The same is true of alloys of lithium and as methylal, glycol formal, and glycerol formal methyl sodium or-by and large-lithium and potassium, so that ether, cyclic ethers such as dioxane, tetrahydrofuran, meth such mixtures, like a lithium, Sodium, and potassium alloy yltetrahydrofuran, tetrahydropyran, methyl tetrahydrofur are ordinarily operable without being specifically advan 60 furyl ether, dimethylenepentaerythritol, and N,N-dimeth tageous. Contact with the solid metals or mixtures there yltetrahydrofurfurylamine; etc. Strictly tertiary amines of can of course be improved by introducing them in a Such as trimethylamine and lower alkyl esters of ortho finely-divided state, but the surfaces tend rapidly to tar acids such as methyl orthoformate and ethyl orthoformate nish as reduction proceeds. have also been used. Moreover, potassium, as distinct So it is that the well-known insolubility of alkali metals 65 from lithium and to a lesser extent sodium, readily forms per se in organic solvents broadly constiutes a substantial adducts in such solvents as diethyl ether, dibutyl ether, and even benzene. Substantial amounts of other relatively deterrent to their “direct' use. Instead, it is preferred inert organic solvents--e.g., toluene, xylene, mineral oil, to employ the metals in the presence of polycyclic aro etc.--may be present without destroying the capacity of matic hydrocarbons such as biphenyl or naphthalene with 70 the foregoing materials to promote adduct formation. which they form soluble adducts Scott et al.: U.S. Despite the widespread operability of preponderantly 2,019,832, U.S. 2,023,793, U.S. 2,027,000, U.S. 2,048,169, ethereal solvents with respect to adduct formation, it will U.S. 2,054,303, and J. Amer. Chem. Soc., 58, 2442 be clear to those skilled in the art that not all such sol (1936), since it turns out that the radical anions deriv vents function equally well as media for the claimed reduc ing from such adducts not only share, but in certain in tion, since not only does their aptitude relate-among 3,274,182 6 other things-to the metal involved, but also to the oper as a convenient means of inducing a desirably rapid ating temperature in prospect. (Most of the lower ali build-up of radical anion concentration, though 1 mole phatic ethers referred to boil at less than 35.) And will probably serve as well if the alkali metal be suf acetals are hydrolyzed by the acid ordinarily introduced ficiently finely-divided. Approximately 1 mole of scaven after reduction is complete, thereby complicating Work-up. ger is preferred, while the optimum amount of solvent is Further, the high reactivity of alkali metal, and the or largely conditioned by the particular reactants involved. ganometallic compounds and radical anions deriving there The reduction of androsta-1,4-diene-3,17-dione 17-ethyl from, practically guarantees that not all of the foregoing ene ketal with lithium and biphenyl in the presence of solvents will be totally impervious to attack thereby under diphenylmethane, using tetrahydrofuran as solvent, is per all conceivable conditions of use; and their Susceptibility O haps most advantageously carried out in 6-10 volumes of to attack is obviously inherently various. Finally, it is solvent, roughly 3 of which are required to dissolve the necessary that the solvent of choice be free from contami ketal. nants which inhibit adduct formation; and the accessibility The build-up of radical anion concentration above rec of such purity likewise varies. Thus, whereas commercial ommended is corollary to the fact that a continuous ex tetrahydrofuran serves admirably as a solvent without any 5 cess of reducing agent in every part of the reaction mix refinement whatever, commercial ethylene glycol dimethyl ture minimizes the opportunity for methyl alkali metal ether is commonly distilled several times over Sodium to to add to the 3-keto group. And it is on this basis, too, render it fit for use and dibutyl ether, in addition, is pre that a preferred technique calls for adding 19-methyl liminarily distilled from a mixture of alumina and Sodium 1,4-dien-3-one to alkali metal or radical anion, rather hydroxide. Most suitable of the various ethereal Solvents 20 than vice versa. evaluated, for the purposes of this invention, are tetra Throughout the course of the reduction, maximally hydrofuran and ethylene glycol dimethyl ether (more effi efficient mixing is maintained; and the reaction mixture ciently named “1,2-dimethoxyethane") admixed, if indi is protected at all times by an inert atmosphere. cated, with such minor amounts of benzene or like rela The 19-nor-3-oxy-1,3,5 (10)-triene produced by the in tively inert organic solvents as may be desirable to insure 25 stant process is a salt which, using the reduction of solubility of the reactants at selected operating tempera androsta-1,4-dien-3-one 17-ethylene ketal as a prototype, tureS. can be enformulated thus The desirability of a scavenger for the methyl alkali metal which is a by-product of the instant process stems from the disposition of the latter to add to the 3-keto 30 group of the steroid being reduced, and is proportional H. CN to the rate of the addition relative to the reduction. In principle, two types of compounds can be used as scaveng ers: those containing functional groups which add to the methyl alkali metal, and those containnig acidic hydrogen 35 atoms which protonate it. In either case, however, the reaction of the scavenger with the methyl alkali metal must be “selective'—which is to say that both reagents M+ O must react appreciably faster with each other than with anything else present in the reaction mixture. Moreover, 40 MF being the cation of the alkali metal employed. Such an effective protonating type scavenger for present pur salts are not ordinarily isolated as such, but instead are poses is necessarily one which will not itself be converted converted to corresponding phenols by acidification. in the course of the protonation to an organometallic com Work-up of the reaction mixture to this end can be ac pound capable of interfering addition to the 3-keto group complished substantially as follows: Organometallic com being reduced. Scavengers best adapted to meet these cri 45 pounds and excess alkali metal are destroyed by the con teria are bulky molecules containing weakly acidic hydro secutive addition of excess methanol and water. When gen atoms such as diphenylmethane and methylnaphtha no more metal remains, an excess of mineral acid is in ene. Homologs thereof wherein one or more alkyl groups troduced and, if ketal groups be present, hydrolysis is replace hydrogen, either on the benzene ring(s) or in the 50 assured by Warming the reactants briefly. Organic sol side chain(s), also will serve. vent is next removed by vacuum distillation, leaving an aqueous Suspension which, assuming a preferred embodi Operating temperatures are largely acritical, albeit in ment of the invention whereby lithium-biphenyl radical tense cold (e.g., -35) is not conductive to maximum anion was the reducing agent in tetrahydrofuran solvent yields in minimal times; and heating above the boiling and with diphenylmethane as scavenger, comprises es point of the reaction mixture tends to be inconvenient. 55 trone, biphenyl and diphenylmethane. The suspension Accordingly, and because within the preferred range thus is triturated with benzene, following which an equal contemplated higher rather than lower temperatures are volume of hexane is added and the resultant mixture al more often advantageous, the process is commonly car lowed to stand until precipitation of estrone is com ried out at reflux. One exception to the usual practice is plete. The estrone is isolated by filtration; further purified made where the radical anion deriving from an adduct of 60 by Washing with 1:1 benzene-hexane, methanol, and lithium an dibenzofuran in tetrahydrofuran is involved, water; and dried in hot air. An additional crop of prod because two Such adducts are possible and only the (green) uct can be isolated by extracting the combined organic one which forms at around 25-in contradistinction to filtrates with aqueous potassium hydroxide and acidifying the (red) one which forms at temperatures approaching the extract. the boiling point of the solvent-affords a radical anion. 65 The following examples describe in detail various ap Various proportions of materials are operable in the plications of the process of this invention in illustrative process; but certain generalizations with respect to op situations. However, the invention is not to be con timum yield, and relative in each instance to the reduc strued as limited thereby, either in spirit or in scope, tion of 1 mole of 19-methyl-1,4-dien-3-one, are in point: since it will be apparent to those skilled in the art that Whereas two gram-atoms of alkali metal are theoretically 70 many modifications, both of materials and of techniques, ideal, 3-4.5 gram-atoms (depending on surface area and may be practiced without departing from the purpose and the size of the run) are more often preferable in prac intent of this disclosure. In the examples hereinafter tice. And although merely a trace of radical anion pre set forth, temperatures are given in degrees centigrade cursor would be ample in the sense that it is not con and relative amounts of materials in parts by weight, ex Sumed in the reaction, 2 moles of precursor are favored 75 cept as otherwise noted. 3,274, 182 7 8 parts of concentrated hydrochloric acid are consecutively Example 1 mixed in under nitrogen. The resultant mixture is To a mixture of approximately 200 parts of a 50% warmed at around 60 for 30 minutes, following which dispersion of lithium in mineral oil and 5400 parts of it is stripped of solvent by vacuum distillation. The tetrahydrofuran at the boiling point under reflux in a 5 residue is suspended in 2250 parts of benzene, whereupon nitrogen atmosphere is added, with agitation during 10 1750 parts of hexane is mixed in and the mixture allowed minutes, a solution of 328 parts of androsta-1,4-diene to stand while estrone separates. The estrone, isolated 3,17-dione 17-ethylene ketal in 1475 parts of tetrahydro by filtration, washed with methanol and water, and dried furan. Boiling under reflux with agitation is continued in warm air, melts at 251-256° (corr.). Extraction of for 1 hour longer, whereupon 800 parts of methanol, O the combined filtrate and washes with aqueous potassium 2000 parts of water, and 1190 parts of concentrated hydroxide, followed by acidification of the extract, af hydrochloric acid is consecutively mixed in, the nitrogen fords additional product. atmosphere being maintained throughout. The resultant mixture is warmed for half an hour, whereupon Solvent Example 6 is removed by vacuum distillation and the residue ex 5 A mixture of 51 parts of lithium wire cut in '4' tracted with benzene. The benzene extract is in turn ex lengths, 950 parts of biphenyl, and approximately 5400 tracted with aqueous 5% potassium hydroxide. From parts of tetrahydrofuran is heated to boiling under re the potassium hydroxide extract, on acidification, estrone flux with agitation in a nitrogen atmosphere while a deep precipitates. Isolated by filtration, washed with water, green color develops. Boiling under reflux with agita and dried in air, the product melts at 249-252 (corr.). 20 tion and protected by nitrogen is continued while a solu tion of 1000 parts of androsta-1,4-diene-3,17-dione 17 Example 2 ethylene ketal in 3600 parts of tetrahydrofuran is intro To a dispersion of 150 parts of sodium in 870 parts duced during 1 hour, care being taken that the green of xylene at 60 is added 4500 parts of tetrahydrofuran. color is always present throughout the reaction mixture The resultant mixture is heated at the boiling point under 25 in process. Thereupon, 790 parts of methanol, 2000 reflux in a nitrogen atmosphere with agitation for 70 parts of water, and 1785 parts of concentrated hydrochlo minutes, during the first 10 of which a solution of 328 ric acid are consecutively mixed in under nitrogen; and parts of androsta-1,4-diene-3,17-dione 17-ethylene ketal the mixture thus obtained is worked up as described in in 1475 parts of tetrahydrofuran is introduced. Work-up Example 5 to give estrone melting at 248-254 (corr.). precisely as described in Example 1 affords estrone melt 30 ing at 251-255 (corr.). Example 7 A procedure identical with that of Example 6 except Example 3 that addition of ketal is effected in 10 minutes rather To a mixture of 250 parts of potassium and 2700 parts than 1 hour affords estrone melting at 244-252 (corr.). of tetrahydrofuran at the boiling point under reflux in 35 a nitrogen atmosphere is added, with agitation and in Example 8 the course of 20 minutes, a solution of 328 parts of A mixture of 14 parts of lithium wire cut in 4' lengths, androsta-1,4-diene-3,17-dione 17-ethylene ketal in 1475 114 parts of biphenyl, and approximately 3400 parts of parts of tetrahydrofuran. During the addition, the color tetrahydrofuran is heated to boiling under reflux with of the reaction mixture ranges from light green to brown. 40 agitation in a nitrogen atmosphere while a deep green Boiling under reflux with agitation is continued for 1 color develops. Boiling under reflux with agitation and hour longer, whereupon work-up as described in Exam protected by nitrogen is continued while a solution of ple 1 affords estrone melting at 234-239 (corr.). 164 parts of androsta-1,4-diene-3,17-dione 17-ethylene Example 4 ketal in approximately 1400 parts of tetrahydrofuran is added in the course of 25 minutes, the addition being To a finely-divided suspension of 140 parts of sodium initially so rapid as to discharge the green color but there and 240 parts of potassium in 5400 parts of tetrahydro after slowed to the point where a yellow color prevails. furan at the boiling point under reflux in a nitrogen at Boiling under reflux with agitation and protected by nitro mosphere is added, with agitation during 45 minutes, a gen is still further continued for 25 minutes, during which solution of 500 parts of androsta-1,4-diene-3,17-dione 17 time the green color reappears. Then, 160 parts of meth ethylene ketal in 2250 parts of tetrahydrofuran. A light anol, 400 parts of water, and 360 parts of concentrated green color prevails throughout. Boiling under reflux hydrochloric acid are mixed in under nitrogen; and the with agitation is continued for a few minutes longer, resultant mixture is warmed at around 60 for 30 min whereupon 800 parts of methanol, 2000 parts of water, utes. Solvent is removed by vacuum distillation. The and 1490 parts of concentrated hydrochloric acid is con residue is suspended in 440 parts of benzene, whereupon secutively mixed in, the nitrogen atmosphere being main 5 5 350 parts of hexane is stirred in. No solid estrone sep tained throughout. Solvent is then removed by vacuum arates. The mixture is extracted with aqueous 5% potas distillation, and the residue is extracted with benzene. sium hydroxide. Acidification affords estrone which, fil The benzene extract is in turn extracted with aqueous tered off, washed with methanol, and dried in air, melts 5% potassium hydroxide. From the potassium hydrox at 248-253. The yield is substantially lower than that ide extract, on acidification, estrone precipitates. Iso 60 obtained by the procedures of Examples 5-7. lated by filtration, washed with water, and dried in air, the product melts at 248-252 (corr.). Example 9 A mixture of 39 parts of potassium, 160 parts of bi Example 5 phenyl, and 900 parts of tetrahydrofuran is heated to A mixture of 71 parts of lithium wire cut in 4' lengths, boiling under reflux with agitation in a nitrogen atmos 941 parts of biphenyl, and approximately 11,000 parts of phere while a deep blue-green color develops. Boiling tetrahydrofuran is heated to boiling under reflux with under reflux with agitation and protected by nitrogen is agitation in a nitrogen atmosphere while a deep green continued while a solution of 160 parts of androsta-1,4- color develops. Boiling under reflux with agitation and diene-3,17-dione 17-ethylene ketal in 675 parts of tetra protected by nitrogen is continued while a solution of 70 hydrofuran is introduced at a rate such that the blue 1000 parts of androsta-1,4-diene-3,17-dione 17-ethylene green color is never discharged (10 minutes required), -ketal in 5400 parts of tetrahydrofuran is introduced at and for 10 minutes thereafter. Then, 160 parts of meth a rate such that the green color is never discharged (30 anol, 400 parts of water, and approximately 240 parts minutes required), and for 10 minutes thereafter. Then, of concentrated hydrochloric acid are consecutively mixed 1580 parts of methanol, 3000 parts of water, and 1785 in under nitrogen. The resultant mixture is warmed 3,274,182 9 O at around 60° for 30 minutes, following which it is stand while estrone separates. The estrone, isolated by stripped of solvent by vacuum distillation. The residue filtration, washed with methanol, and dried in warm air, is supended in 450 parts of benzene, whereupon 660 parts melts at 239-245 (corr.). Extraction of the combined of hexane is mixed in and the mixture allowed to stand filtrate and wash with aqueous potassium hydroxide, fol briefly while estrone separates. The estrone, isolated by 5 lowed by acidification of the extract, affords additional filtration, washed with methanol, and dried in warm air, product. melts at 246-252 (corr.). Extraction of the combined filtrate and wash with aqueous potassium hydroxide, Example 13 followed by acidification of the extract, affords additional A mixture of 7 parts of lithium wire cut in 4' product. lengths, 85 parts of redistilled 1-methylnaphthalene, and Example 10 10 540 parts of tetrahydrofuran is heated to boiling under A mixture of approximately 29 parts of sodium, 74 reflux with vigorous agitation in a nitrogen atmosphere parts of potassium, 156 parts of biphenyl, and 900 parts while a green color develops. Boiling under reflux with of tetrahydrofuran is heated to boiling under reflux with vigorous agitation and protected by nitrogen is continued agitation in a nitrogen atmosphere while a green color 15 while a solution of 50 parts of androsta-1,4-diene-3,17 develops. Boiling under reflux with agitation and pro dione 17-ethylene ketal in 225 parts of tetrahydrofuran tected by nitrogen is continued while a solution of 164 is introduced at a rate such that the green color is never parts of androsta-1,4-diene-3,17-dione 17-ethylene ketal discharged (35 minutes required), and for 10 minutes in approximately 720 parts of tetrahydrofuran is intro thereafter. Then, 80 parts of methanol, 200 parts of duced at a rate such that the green color is never dis 20 water, and approximately 110 parts of concentrated hy charged (30 minutes required), whereupon 400 parts of drochloric acid are consecutively mixed in under nitrogen. methanol, 500 parts of water, and approximately 300 The resultant mixture is warmed at around 60° for 30 parts of concentrated hydrochloric acid are consecutively minutes, following which it is stripped of solvent by vac mixed in under nitrogen. The resultant mixture is uum distillation. The residue is suspended in 90 parts warmed briefly, following which it is stripped of solvent 25 of benzene whereupon 104 parts of hexane is mixed in by vacuum distillation. The residue is mixed with 1750 and the mixture allowed to stand overnight while estrone parts of ether and the insoluble estrone filtered from the separates. The estrone, isolated by filtration, washed mixture, washed on the filter with methanol, and dried with methanol, and dried in warm air, melts at 250-256 in warm air. The combined filtrate and wash is extracted (corr.). Extraction of the combined filtrate and wash with aqueous 5% potassium hydroxide. Acidification 30 with aqueous potassium hydroxide, followed by acidifica affords additional estrone. The product melts at 244 tion of the extract, affords additional product. Total 252 (corr.). yield is approximately 74% of theory. Example II Example 14 A mixture of 5 parts of lithium wire cut in 4' 35 A mixture of 14 parts of lithium wire cut in 4' lengths, lengths, 78 parts of naphthalene, and 270 parts of tetra 172 parts of dibenzofuran, and approximately 1700 parts hydrofuran is heated to boiling under reflux with vigorous of tetrahydrofuran is maintained with vigorous agitation agitation in a nitrogen atmosphere while a deep green at room temperatures under nitrogen until a green color color develops. Boiling under reflux with vigorous agi develops. A solution of 164 parts of androsta-1,4-diene tation and protected by nitrogen is continued while a 40 3,17-dione 17-ethylene ketal in 900 parts of tetrahydro solution of 100 parts of androsta-1,4-diene-3,17-dione furan is thereupon introduced, under nitrogen, at a rate 17-ethylene ketal in 360 parts of tetrahydrofuran is in Such that the green color is never discharged. Agitation troduced at a rate such that the green color is never under nitrogen at room temperatures is continued for 30 discharged, 10 minutes being required. Then, 160 parts minutes following completion of the addition, at which of methanol, 300 parts of water, and approximately 180 45 point 800 parts of methanol, 2000 parts of water, and parts of concentrated hydrochloric acid are consecutively approximately 600 parts of concentrated hydrochloric mixed in under nitrogen. The resultant mixiture is acid are consecutively mixed in under nitrogen. The re warmed at around 60° for 30 minutes, following which Sultant mixture is warmed at around 60 for 30 minutes, it is stripped of solvent by vacuum distillation. The following which it is stripped of solvent by vacuum dis residue is suspended in 225 parts of benzene, whereupon 50 tillation. The residue is suspended in 3500 parts of ether approximately 175 parts of hexane is mixed in and the and the suspension allowed to stand briefly until no more mixture allowed to stand briefly while estrone separates. estrone separates. The estrone, isolated by filtration, The estrone, isolated by filtration, washed with methanol Washed with methanol and water, and dried in warm air, and water, and dried in warm air, melts at 250-253 melts at 264-266. Extraction of the combined filtrate (corr.). Extraction of the combined filtrate and washes 55 and washes with aqueous potassium hydroxide, followed with aqueous potassium hydroxide, followed by acidi by acidification of the extract, affords additional product fication of the extract, affords additional product. melting at 245-250. Example 12 Example 15 A mixture of 14 parts of sodium, 42 parts of naptha 60 A mixture of 7 parts of lithium wire cut in 4' lengths, lene, and 540 parts of tetrahydrofuran is heated to boil 85 parts of 1-methylnaphthalene, 52 parts of diphenyl ing under reflux with vigorous agitation in a nitrogen methane, and 540 parts of tetrahydrofuran is heated to atmosphere while a green color develops. Boiling under boiling under reflux with vigorous agitation in a nitrogen reflux with vigorous agitation and protected by nitrogen atmosphere while a deep green color develops. Boiling is continued while a solution of 50 parts of androsta-1,4- 65 under reflux with vigorous agitation and protected by diene-3,17-dione 17-ethylene ketal in 225 parts of tetrahy nitrogen is continued while a solution of 50 parts of drofuran is introduced at a rate such that the green color androsta-1,4-diene-3,17-dione 17-ethylene ketal in 225 is never discharged, about 10 minutes being required. parts of tetrahydrofuran is introduced at a rate such that Then, 40 parts of methanol, 100 parts of water, and 120 the green color is never discharged (30 minutes required), parts of concentrated hydrochloric acid are consecutively 70 and for 10 minutes thereafter. Then, 80 parts of metha mixed in under nitrogen. The resultant mixture is nol, 200 parts of water, and 150 parts of concentrated warmed at around 60° for 30 minutes, following which it hydrochloric acid are consecutively mixed in under nitro is stripped of solvent by vacuum distillation. The resi gen. The resultant mixture is warmed at around 60° due is suspended in 135 parts of benzene, whereupon 105 for 30 minutes, following which it is stripped of solvent parts of hexane is mixed in and the mixture allowed to 75 by vacuum distillation. The residue is suspended in 90 3,274,182 2 parts of benzene, whereupon approximately 105 parts Example 18 of hexane is mixed in and the mixture allowed to stand briefly while estrone separates. The estrone, isolated by A scrupulously cleaned and dried stainless steel reac filtration, washed with methanol, and dried in Warm air, tor is charged with 20,800 parts of biphenyl, 11,480 melts at 248-252 (corr.). Extraction of the combined parts of diphenylmethane, and approximately 120,000 filtrate and wash with aqueous potassium hydroxide, foll parts of tetrahydrofuran. The reactor is evacuated and lowed by acidification of the extract, affords additional purged with nitrogen. All subsequent operations down product. The total yield is 82% of theory. to and including acidification are conducted in a nitrogen atmosphere with vigorous agitation. The reaction mix Example I6 ture is heated to reflux, whereupon heating is stopped A mixture of 31 parts of lithium wire cut in 4' lengths, O and 46,040 parts of a 30% dispersion of lithium in 850 parts of 2-methylnaphthalene, 260 parts of diphenyl paraffin is charged portionwise, Small increments being methane, and 5400 parts of tetrahydrofuran is heated to added until the mixture turns green and the balance be boiling under reflux with vigorous agitation in a nitrogen ing added as rapidly as foaming will permit. A Solution atmosphere while a deep green color develops. Boiling 15 of 22,050 parts of androsta-1,4-diene-3,17-dione 17 under reflux with vigorous agitation and protected by ethylene ketal in 63,000 parts of hot tetrahydrofuran is nitrogen is continued while a Solution of 500 parts of filtered and divided in halves. The first half is charged androsta-1,4-diene-3,17-dione 17-ethylene ketal in 2250 as rapidly as maintenance of the green color (and a con parts of tetrahydrofuran is introduced at a rate such that siderable heat effect) will permit, whereupon 2300 parts the green color is always present, approximately 30 min 20 of a 30% dispersion of lithium in paraffin is charged as utes being required. Consecutive introduction of 800 rapidly as possible in view of the foaming previously parts of methanol, 2000 parts of water, and 1500 parts noted. The reaction mixture is then reheated to reflux of concentrated hydrochioric acid under nitrogen, foll and the balance of the ketal solution charged again, as lowed by warming at around 60 for 30 minutes and Sub rapidly as is consistent with the maintenance of the green sequent stripping of solvent by vacuum distillation, affords color. Reflux is continued for 15 minutes, at which residue which is suspended in benzene. From the benzene point 2800 parts of methanol is cautiously added, fol suspension, insoluble estrone is separated by filtration, lowed by 70,000 parts of water. The reaction mixture washed with methanol, and dried in air. Extraction of is then transferred to a glass-lined still pot and acidified the combined filtrate and Wash with aqueous potassium with approximately 45,800 parts of concentrated hydro hydroxide, followed by acidification of the extract, affords chloric acid. The resultant mixture is heated at near additional product. Total yield is approximately 83% boiling for 30 minutes with agitation, then freed of tetra theory. hydrofuran and methanol by vacuum distillation. The Example 17 aqueous phase is decanted from the residue, and the granular solids are mixed with approximately 49,000 To a solution of 660 parts of biphenyl and 364 parts 35 parts of benzene during 10 minutes. This mixture in of diphenylmethane in approximately 3800 parts of tetra turn is mixed with approximately 37,000 parts of hexane hydrofuran under nitrogen is added 44 parts of lithium for 10 minutes; and the resultant mixture is allowed to wire cut in 4' lengths. A dark green color rapidly stand overnight. The insoluble estrone is filtered off and appears on the freshly-cut surfaces of the lithium. The washed on the filter with 1:1 benzene-hexane, then mixture is refluxed under nitrogen with vigorous agitation 40 slurried with methanol and again isolated by filtration. until the green color permeates the reaction mixture, at Additional estrone is obtained by extracting the combined which point a solution of 700 parts of androsta-1,4-diene 3,17-dione 17-ethylene ketal in approximately 2100 parts filtrates and washes with aqueous potassium hydroxide of warm tetrahydrofuran is introduced during approxi and acidifying the extract. mately 70 minutes, the addition rate being so controlled Example 19 as to insure that the green color is maintained at all times. 45 A mixture of 7 parts af lithium wire cut in 4' lengths, Heat is evolved. When addition of the ketal solution is 100 parts of biphenyl, and 540 parts of tetrahydrofuran complete, reflux under nitrogen with vigorous agitation is heated to boiling under reflux with vigorous agitation is continued for 15 minutes, whereupon 560 parts of in a nitrogen atmosphere while a green color develops. methanol is cautiously added (with agitation under nitro Boiling under reflux with vigorous agitation and pro gen). After approximately half the methanol has been 50 tected by nitrogen is continued while a solution of 50 added, the reaction mixture becomes quite thick, thinning parts of androsta-1,4-diene-3,17-dione 17-ethylene ketal out again as the balance is introduced. Much heat is and 204 parts of diphenylmethane in 225 parts of tetra evolved. Approximately 1400 parts of water is next hydrofuran is added at a rate such that the green color cautiously added (with agitation under nitrogen), the is not discharged, approximately 25 minutes being re viscosity of the reaction mixture tending to vary as during 55 quired. Consecutive addition under nitrogen of 80 parts the methanol addition. Initially, Substantial heat is of methanol, 200 parts of water, and approximately 85 evolved. When all of the water has been added, approxi parts of concentrated hydrochloric acid, followed by mately 800 parts of concentrated hydrochloric acid is heating at approximately 60° for 30 minutes and sub cautiously mixed in. Sufficient heat is evolved to bring sequent removal of solvent by vacuum distillation, af the mixture to boiling. The mixture is maintained with 60 fords a residue which is taken up in 180 parts of benzene. agitation at the elevated temperature for 30 minutes, then Approximately 210 parts of hexane is mixed in and the freed of tetrahydrofuran and methanol by vacuum distill mixture allowed to stand while estrone separates. Iso lation. The mushy residue is suspended in approximately lated by filtration, washed on the filter with methanol 1500 parts of benzene, care being taken that no large and then with water, and dried in warm air, the product lumps remain. Then approximately 1100 parts of hexane 65 melts at 250-260 (corr.). is stirred in. When separation of estrone from the mix ture is complete, it is filtered off and consecutively rinsed Example 20 with 1:1 benzene-hexane, methanol, water, and methanol. A mixture of 10 parts of lithium wire cut in 4' Dried in warm air, the product melts at 258-261. The lengths, 100 parts of biphenyl, 51 parts of diphenyl filtrate is diluted with water and the benzene-hexane layer 70 methane, and approximately 1100 parts of tetrahydro separated and extracted with aqueous 5% potassium hy furan is heated to boiling under reflux with vigorous droxide. Acidification of this extract affords additional agitation in a nitrogen atmosphere while a deep blue estrone melting at 260-265. By the foregoing proce green color develops. Boiling under reflux with vigor dure, yields of pure product ranging upward of 77% ous agitation and protected by nitrogen is continued theory are achieved. 75 while a solution of 100 parts of androsta-1,4-diene-3,17

w 3,274,182 3 dione 17-ethylene ketal in 450 parts of tetrahydrofuran minutes, following which it is stripped of solvent by is introduced at a rate such that the blue-green color re Vacuum distillation. The residue is consecutively mixed mains undischarged (approximately 30 minutes), and for with 1170 parts of benzene and 910 parts of hexane. No a few minutes longer. Then, 160 parts of methanol, 300 estrone separates at this point. Extraction with aqueous parts of water, and 150 parts of concentrated hydro 5% potassium hydroxide and acidification of the extract chloric acid are consecutively mixed in under nitrogen. affords an insubstantial yield of estrone. The resultant mixture is warmed at around 60' for 30 minutes, following which it is stripped of solvent by Example 25 vacuum distillation. The residue is mixed with 210 parts Approximately 26 parts of lithium wire cut in 4' of ether. Estrone is separated therefrom by filtration. O lengths, 386 parts of biphenyl, 220 parts of diphenyl The product is further purified by rinsing with methanol. methane, and 2250 parts of tetrahydrofuran are mixed at room temperature under nitrogen and held there with Example 21 vigorous agitation until a deep green color develops. The Substitution of 12 parts of lithium and 204 parts of mixture is then cooled to 0 and maintained thereat with diphenylmethane for the 10 parts of lithium and 51 parts vigorous agitation under nitrogen while a solution of 400 of diphenylmethane called for in the preceding Example parts of androsta-1,4-diene-3,17-dione 17-ethylene ketal in 20 affords, by the procedure there detailed, substantially 1350 parts of tetrahydrofuran is added at a rate such that the same yield and purity of estrone. the green color is not discharged (approximately 30 min Example 22 utes required). Then, 2400 parts of methanol, 2000 parts 20 of water, and 600 parts of concentrated hydrochloric acid A mixture of 6 parts of lithium wire cut in 4' lengths, are consecutively mixed in under nitrogen. The resultant 25 parts of biphenyl, 26 parts of diphenylmethane, and mixture is warmed at around 60 for 30 minutes, follow 270 parts of tetrahydrofuran is heated to boiling under ing which it is stripped of solvent by vacuum distillation. reflux with vigorous agitation in a nitrogen atmosphere The residue is consecutively mixed with 1170 parts of while a deep green color develops. Boiling under reflux 25 benzene and 910 parts of hexane. Insoluble solids (in with vigorous agitation and protected by nitrogen is con this instance not estrone) are filtered off and discarded, tinued while a solution of 50 parts of androsta-1,4-diene and the filtrate is extracted with aqueous 5% potassium 3,17-dione 17-ethylene ketal in 225 parts of tetrahydro hydroxide. Acidification of the potassium hydroxide ex furan is introduced at a rate such that the green color is tract affords a relatively low yield of crude estrone as a not discharged (approximately 30 minutes required), 30 precipitate which, filtered off and dried in air, melts at and for 10 minutes thereafter. Then, 80 parts of meth 245-258. anol, 200 parts of water, and 150 parts of concentrated Example 26 hydrochloric acid are consecutively mixed in under nitro Approximately 63 parts of lithium wire cut in 4' gen. The resultant mixture is warmed at around 60 lengths, 940 parts of biphenyl, 520 parts of diphenyl for a few minutes, following which it is stripped of sol 35 methane, and 5400 parts of tetrahydrofuran are mixed at vent by vacuum distillation. The residue is suspended 18-20 under nitrogen to form a deep green solution and in 680 parts of heptane and the suspension allowed to maintained thus with vigorous agitation during addition stand while estrone separates. The product is filtered of a solution of 1000 parts of androsta-1,4-diene-3,17 off, washed on the filter with methanol, and dried in air. dione 17-ethylene ketal in approximately 2900 parts of Example 23 40 Warm tetrahydrofuran at a rate such that the green color is never discharged (30 minutes required). The described A mixture of 21 parts of lithium wire cut in 4' lengths, conditions are further maintained for 30 minutes, where 250 parts of biphenyl, 260 parts of diphenylmethane, and upon 800 parts of methanol, 2000 parts of water, and 1200 1350 parts of tetrahydrofuran is heated to boiling under parts of concentrated hydrochloric acid are consecutively reflux with vigorous agitation in a nitrogen atmosphere mixed in under nitrogen. The resultant mixture is while a green color develops. Boiling under reflux with warmed at 50 for 30 minutes, following which it is vigorous agitation and protected by nitrogen is continued stripped of solvent by vacuum distillation. The residue while a solution of 500 parts of androsta-1,4-diene-3,17 is consecutively mixed with 2000 parts of benzene and dione 17-ethylene ketal in 2250 parts of tetrahydrofuran is 1750 parts of hexane, whereupon the insoluble estrone is added at a rate such that the green color is not discharged 50 filtered therefrom and consecutively washed on the filter (25 minutes required), and for 10 minutes thereafter. with 1:1 benzene-hexane, methanol, water, and methanol. Then, 800 parts of methanol, 2000 parts of water, and The combined filtrate and washes are extracted with aque 1800 parts of concentrated hydrochloric acid are consecu Ous 5% potassium hydroxide. Acidification of the ex tively mixed in under nitrogen. The resultant mixture is tract affords additional estrone. The total yield of prod warmed at around 60 for 30 minutes, following which it 55 luct by this procedure is relatively modest. is stripped of solvent by vacuum distillation. The residue is suspended in approximately 1400 parts of heptane. The Example 27 suspension is set aside until no more estrone separates, Changing the operating temperature from 18-20° to whereupon the product is isolated by filtration, washed on approximately 35 but otherwise duplicating the proce the filter with methanol, and dried in warm air. It melts 60 dure of Example 26 affords an improved yield of product at 240-250 (corr.). melting at 249-253°. Example 24 Example 28 Approximately 28 parts of lithium, 470 parts of bi Changing the operating temperature from 18–20° to phenyl, 260 parts of diphenylmethane, and 4500 parts of approximately 50 but otherwise duplicating the proce tetrahydrofuran are mixed at room temperature under 65 dure of Example 26 affords a substantially optimal yield nitrogen and held there with vigorous agitation while a of estrone. The product melts at 248-251. deep green color develops. The mixture is then cooled to -35 and maintained thereat with vigorous agitation Example 29 under nitrogen while a solution of 500 parts of androsta A mixture of 21 parts of lithium wire cut in 4' 1,4-diene-3,17-dione 17-ethylene ketal in 2700 parts of 70 lengths, 268 parts of phenanthrene, 128 parts of diphenyl tetrahydrofuran is added at a rate such that the green methane, and 1800 parts of tetrahydrofuran is warmed color is not discharged. Then, 2400 parts of methanol, With vigorous agitation under nitrogen while a muddy 2000 parts of water, and 600 parts of concentrated hy green color develops. The mixture is heated at the boil drochloric acid are consecutively mixed in under nitrogen; ing point under reflux with vigorous agitation and pro and the resultant mixture is warmed at around 60 for 30 75 tected by nitrogen while a solution of 250 parts of an pr

3,274,182 5 16 drosta-1,4-diene-3,17-dione 17-ethylene ketal in 810 parts Example 32 of warm tetrahydrofuran is introduced at a rate such that A mixture of 21 parts of lithium wire cut in 4' the green color is not discharged (30 minutes required). lengths, 265 parts of anthracene, 128 parts of diphenyl At this point, 200 parts of methanol, 500 parts of water, methane, and 1800 parts of tetrahydrofuran is warmed and 300 parts of concentrated hydrochloric acid are con with vigorous agitation under nitrogen while a deep blue secutively mixed in under nitrogen. The resultant mix color develops. The mixture is heated at the boiling ture is warmed at 55 for 20 minutes, following which it point under reflux with vigorous agitation and protected is stripped of solvent by vacuum distillation. The resi by nitrogen while a solution of 250 parts of androsta due is consecutively mixed with 675 parts of benzene and 1,4-diene-3,17-dione 17-ethylene ketal in 810 parts of 525 parts of hexane, whereupon insoluble estrone is fil O Warm tetrahydrofuran is introduced at a rate such that tered off, washed with methanol, and dried in warm air. the color is not discharged, though it changes to muddy Extraction of the combined filtrate and wash with aque green (30 minutes). At this point, 200 parts of methanol, ous 5% potassium hydroxide, followed by acidification 500 parts of water, and 300 parts of concentrated hy of the extract, affords additional product. The estrone drochloric acid are consecutively mixed in under ni thus obtained melts at 245-255. Total yield is 82% 15 trogen. The resultant mixture is warmed at 55 for theory. 20 minutes, following which it is stripped of solvent by Example 30 vacuum distillation. The residue is consecutively mixed A mixture of 31 parts of lithium wire cut in 4' with 675 parts of benzene and 525 parts of hexane. No lengths, 370 parts of o-terphenyl, 260 parts of diphenyl 20 estrone separates. The mixture is extracted with aque methane, and 5400 parts of tetrahydrofuran is heated ous 5% potassium hydroxide. Acidification affords es to boiling under reflux with vigorous agitation in a trone melting at 245-260. The yield is 17% theory. nitrogen atmosphere while a deep green color develops. Example 33 Boiling under reflux with vigorous agitation and pro To a solution of 463 parts of acenaphthene in 2700 tected by nitrogen is continued while a solution of 500 25 parts of tetrahydrofuran under nitrogen is added, with parts of androsta-1,4-diene-3,17-dione 17-ethylene ketal vigorous agitation, 28 parts of lithium wire cut in 4' in 2250 parts of tetrahydrofuran is introduced at a rate lengths. The reaction mixture becomes muddy green in such that the green color is not discharged. Then, 800 color. It is heated to the boiling point under reflux and parts of methanol, 2000 parts of water, and 1200 parts still protected by nitrogen while 260 parts of diphenyl of concentrated hydrochloric acid are consecutively mixed 30 methane and then a solution of 500 parts of androsta-1,4- in under nitrogen. The mixture is warmed at 60° for diene-3,17-dione 17-ethylene ketal in 2250 parts of tetra 30 minutes, following which it is stripped of solvent hydrofuran are added with vigorous agitation, the ketal by vacuum distillation. The residue is suspended in addition requiring approximately 30 minutes. When 1130 parts of benzene, whereupon 875 parts of hexane is about 4 the ketal has been introduced, 10 more parts of mixed in and the mixture allowed to stand while estrone 35 finely-cut lithium wire is added to insure maintenance separates. The estrone, isolated by filtration, washed of the green color. To the resultant mixture are con with methanol and water, and dried in warm air, melts secutively added, with continued vigorous agitation and at 253-259 (corr.). Extraction of the combined fil trate and washes with aqueous 5% potassium hydroxide, protected by nitrogen, 400 parts of methanol, 1000 parts 40 of water, and 600 parts of concentrated hydrochloric followed by acidification of the extract affords additional acid. The resultant mixture is warmed at 60' for 30 product. Total yield is 72% theory. minutes, then stripped of solvent by vacuum distillation. The residual oil is dissolved in a mixture of benzene and Example 31 hexane (1170 and 910 parts, respectively). No solid A mixture of 64 parts of a 50% dispersion of lithium 45 separates. Extraction of the solution with aqueous 5% in paraffin, 700 parts of p-terphenyl, 256 parts of di potassium hydroxide and acidification of the extract phenylmethane, and 2700 parts of tetrahydrofuran is affords a gummy precipitate of estrone which, filtered off heated to the boiling point with vigorous agitation in and consecutively washed with methanol and ether, then a nitrogen atmosphere. Initially, a black-green color dried in air, sinters at 250 and melts at 255-260. The develops, which changes to dark green as the temperature 50 yield is approximately 6% theory. approaches the boiling point. Boiling under reflux with Example 34 vigorous agitation and protected by nitrogen is continued while a solution of 500 parts of androsta-1,4-diene-3,17 To a mixture of 490 parts of fluoranthene with 2700 dione 17-ethylene ketal in approximately 1500 parts of parts of tetrahydrofuran under nitrogen is added, with hot tetrahydrofuran is added during the course of /2 55 vigorous agitation, 28 parts of lithium wire cut in short hour. The green color fades during the addition, the pieces. The resultant green mixture is heated at the mixture becomes darker, and by the time all of the ketal boiling point under nitrogen with vigorous agitation has been introduced it is no longer possible to detect while 260 parts of diphenylmethane is introduced, fol a greenish cast. At this point, 800 parts of methanol, lowed by a solution of 480 parts of androsta-1,4-diene 1000 parts of water, and 840 parts of concentrated hy 60 3,17-dione 17-ethylene ketal in 2250 parts of tetrahydro drochloric acid are consecutively mixed in under nitro furan at a rate such that the green color is continuously gen. The resultant mixture is warmed at around 60 maintained. Approximately 30 minutes are required for for 30 minutes, then stripped of solvent by vacuum dis the ketal addition. At this point, 400 parts of methanol, tillation. The residue is suspended in 2250 parts of 1000 parts of water, and 600 parts of concentrated hydro benzene, following which the insoluble solids are filtered 65. chloric acid are consecutively mixed in under nitrogen. off, consecutively rinsed with benzene and methanol, and The resultant mixture is heated at 60 for 30 minutes, extracted with 5% potassium hydroxide in 2:1 water then stripped of solvent by vacuum distillation. The resi methanol. Acidification of the extract affords a finely due is dissolved in a mixture of 1170 parts of benzene divided precipitate of estrone which, isolated by filtration, and 910 parts of hexane. No solid precipitates from the washed with water, and dried in warm air, sinters in the 70 solution. The solution is extracted with aqueous 5% range 220-250 and melts at 250-258. Extraction of potassium hydroxide, and the extract is acidified. Crys the original benzene filtrate with aqueous potassium hy talline estrone is thrown down. The product is recovered droxide and acidification of the extract affords an addi on a filter, washed thereon with ether, and dried in air. tional crop of estrone. The total yield of product is It melts in the range 240-260. The yield is approxi 68% theory. 5 mately 7% theory. 3,274,182 17 18 Example 35 ture is consecutively mixed under nitrogen with 80 parts A mixture of 12 parts of lithium wire cut in 14' during the ketal addition, and reappears only slowly. By lengths, 82 parts of recrystallized naphthalene, 51 parts of of methanol, 200 parts of water, and approximately 360 diphenylmethane, and approximately 1100 parts of tetra parts of concentrated hydrochloric acid. The mixture hydrofuran is heated to boiling under reflux with vigorous thus obtained is warmed at 60 for 30 minutes, following agitation in a nitrogen atmosphere while a deep green which it is stripped of solvent by vacuum distillation. color develops. Boiling under reflux with vigorous agita The residue is suspended in 225 parts of benzene, where tion and protected by nitrogen is continued while a solu upon 175 parts of hexane is mixed in and the mixture tion of 100 parts of androsta-1,4-diene-3,17-dione 17 allowed to stand while estrone separates. The estrone, ethylene ketal in 450 parts of tetrahydrofuran is added O isolated by filtration, washed with methanol, and dried at a rate such that the green color is never discharged in warm air, melts at 250-259. (20 minutes required), and for 20 minutes thereafter. Example 39 Then, 160 parts of methanol, 300 parts of water, and 150 parts of concentrated hydrochloric acid are consecutively Approximately 28 parts of lithium wire in small pieces mixed in under nitrogen. The resultant mixture is main is vigorously agitated with a solution of 308 parts of bi tained with agitation at its own temperature for 1 hour, phenyl and 140 parts of diphenylmethane in 255 parts of whereupon solvent is removed by vacuum distillation. 2-methyltetrahydrofuran at about 5 under nitrogen until The residue is suspended in 210 parts of ether, and the a deep green color appears, whereupon the reactants are Suspension is allowed to stand until separation of estrone chilled at 0-3 with vigorous agitation under nitrogen is complete. The product is filtered off, rinsed on the 20 while a solution of 328 parts of androsta-1,4-diene-3,17 filter with 1:1 ether methanol, and dried in air. Extrac dione 17-ethylene ketal in a mixture of 175 parts of 2 tion of the combined filtrate and rinse with aqueous methyltetrahydrofuran and 45 parts of benzene is added potassium hydroxide, followed by acidification of the during 70 minutes. The green color is easily discharged extract, affords additional product. Yield is 78% theory. the time all of the ketal has been added, the reaction 25 mixture has become brown. However, it becomes green Example 36 again after stirring 5 more minutes. At this point, 800 Substitution of 273 parts of benzophenone for the an parts of methanol, 2000 parts of water, and 1200 parts of thracene called for in Example 32, and use of 28 parts of concentrated hydrochloric acid are consecutively mixed lithium wire, 600 parts of methanol, and 2000 parts of 30 in under nitrogen. The resultant mixture is warmed at water rather than the amounts of these materials specified 60 for 30 minutes, then stripped of solvent by vacuum therein affords, by a procedure otherwise identical, ap distillation. The residue is mixed with 900 parts of ben proximately 8% the theoretical yield of estrone melting Zene and 700 parts of hexane. Insoluble solids are fil tered off and discarded, since infrared analysis and the at 252-257. melting point indicate they are not estrone. The filtrate Example 37 35 is extracted with aqueous 5% potassium hydroxide, and A mixture of 14 parts of lithium wire cut in 4' the extract is acidified. A small amount of crude estrone lengths, 160 parts of biphenyl, 85 parts of diphenyl (M.P. 255-258) is precipitated. methane, and approximately 870 parts of 1,2-dimethoxy ethane preliminarily distilled over potassium is heated to Example 40 40 boiling under reflux with vigorous agitation in a nitrogen (A) A mixture of 284 parts of androsta-1,4-diene-3,17 atmosphere while a deep green color develops. Boiling dione, 284 parts of 1,2-propanediol, 1 part of p-toluene under reflux with vigorous agitation and protected by Sulfonic acid and 2560 parts of benzene is heated at the nitrogen is continued while a slurry of 160 parts of boiling point under reflux with agitation for two hours, androsta-1,4-diene-3,17-dione 17-ethylene ketal in ap water being removed as formed. The reaction mixture proximately 870 parts of 1,2-dimethoxyethane is intro 45 is then cooled and neutralized with aqueous 10% potas duced at a rate such that the color remains undischarged sium bicarbonate, whereupon the benzene phase is sepa (50 minutes required), and for 10 minutes thereafter. rated, washed with water, and stripped of solvent by Then, 160 parts of methanol, 400 parts of water, and 360 vacuum distillation. Trituration of the residue with parts of concentrated hydrochloric acid are consecutively ether affords androsta-1,4-diene-3,17-dione 17-propylene mixed in under nitrogen. The mixture thus obtained is 50 ketal melting at 161-167 (corr.). warmed for 1/2 hour and then stripped of solvent by vac (B) Estrone of comparable yield and purity to that uum distillation. The residue is suspended in 700 parts obtained, for instance, by the procedure of Example 17 of hexane and the suspension set aside until precipitation is produced by substituting for the 700 parts of androsta of estrone is complete. The estrone is collected on a 1,4-diene-3,17-dione 17-ethylene ketal therein 729 parts filter, rinsed thereon with hexane and methanol, and dried 55 of androsta-1,4-diene-3,17-dione 17-propylene ketal. in air. It melts 250-254 (corr.). Extraction of the combined filtrate and rinses with aqueous potassium hy Example 41 droxide, followed by acidification of the extract, affords (A) Substitution of 284 parts of 1,3-propanediol and adiditional product. Total yield is around 72% theory. 1750 parts of hexane for the 1,2-propanediol and 256 Example 38 60 parts of benzene, respectively, called for in Example 40A Approximately 23 parts of lithium wire in small pieces affords, by the procedure there detailed, androsta-1,4- is vigorously agitated with a solution of 94 parts of bi diene-3,17-dione 17-trimethylene ketal melting at 118 phenyl and 52 parts of diphenylmethane in 510 parts of 123 (corr.). 2-methyltetrahydrofuran at room temperatures under 65 (B) Estrone of comparable yield and purity to that nitrogen until a deep green color develops, whereupon obtained, for instance, by the procedure of Example 17 the reactants are refluxed with vigorous agitation under is produced by substituting for the 700 parts of androsta nitrogen while a solution of 100 parts of androsta-1,4- 1,4-diene-3,17-dione 17-ethylene ketal called for therein diene-3,17-dione 17-ethylene ketal in 420 parts of hot 729 parts of androsta-1,4-diene-3,17-dione 17-trimethyl 2-methyltetrahydrofuran is added during 1 hour. Within 70 ene ketal. the first 10 minutes of heating, the color changes to a Example 42 muddy green, probably as a result of interaction between (A) A mixture of 284 parts of androsta-1,4-diene-3,17 2-methyltetrahydrofuran and lithium-biphenyl. When dione, 416 parts of 2,2-dimethyl-1,3-propanediol, 10 parts approximately 4 of the ketal solution has been added, of p-toluenesulfonic acid, and 5200 parts of benzene is the green fades to a reddish-brown. The resultant mix 75 heated at the boiling point under reflux with agitation for 3,274,182 19 20 2/2 hours, water being removed as formed. The reaction (B) Substitution of 185 parts of 176-(2-tetrahydro mixture is then cooled, and 500 parts of aqueous 10% pyranyloxy)androsta-1,4-dien-3-one for the 176-hydroxy potassium bicarbonate is added thereto. The benzene androsta-1,4-dien-3-one called for in Example 44 affords, phase is separated, washed with water, dried over anhy by the procedure there detailed, a somewhat better yield drous sodium sulfate, and stripped of solvent by vacuum of 176-estradiol. distillation. The residue, recrystallized from 1:3 water Example 46 methanol, affords androsta-1,4-diene-3,17-dione 17-(2,2'- dimethyltrimethylene) ketal melting at 150-152 (corr.). A mixture of 10 parts of lithium wire cut in small (B) Estrone of comparable yield and purity to that pieces, 100 parts of biphenyl, 54 parts of diphenylmethane, obtained, for instance, by the procedure of Example 17 10 and 900 parts of tetrahydrofuran is heated to boiling is produced by substitution for the 700 parts of androsta under reflux with vigorous agitation in a nitrogen atmos 1,4-diene-3,17-dione 17-ethylene ketal called for therein phere while the characteristic deep color develops. Boil 778 parts of androsta-1,4-diene-3,17-dione 17-(2,2'-di ing under reflux with vigorous agitation and protected by methyltrimethylene) ketal. nitrogen is continued while a solution of 100 parts of 5 17o-ethyl-17 3-hydroxyandrosta-1,4-dien-3-one in 675 parts Example 43 of hot tetrahydrofuran is introduced during 35 minutes, A mixture of 147 parts of lithium wire cut in 4' and for 15 minutes thereafter. Approximately 240 parts lengths, 1080 parts of biphenyl, 588 parts of diphenyl of methanol, 80 parts of water, and 100 parts of glacial methane, and 5400 parts of tetrahydrofuran is heated to acetic acid and thereupon consecutively mixed in under boiling under reflux in a nitrogen atmosphere while a 20 nitrogen. The organic solvents are removed by vacuum green color develops. Boiling under reflux with vigorous distillation, and the residue is titurated with 350 parts of agitation and protected by nitrogen is then continued ether. The insoluble solid is 17a-ethylestra-1,3,5(10)- while a solution of 1000 parts of androsta-1,4-diene-3,17 triene-3,176-diol, which is isolated by filtration, further dione in 2925 parts of warm tetrahydrofuran is introduced purified by washing on the filter with ether and water, at a rate such that the green color is not discharged, 25 - and dried in air. approximately 30 minutes being required. Thereupon, Example 47 1600 parts of methanol, 4000 parts of warm water, and 3000 parts of concentrated hydrochloric acid are con (A) A stainless steel fermentation tank is charged with secutively mixed in under nitrogen. Solvent is stripped a nutrient medium consisting of 75 parts of commercial by vacuum distillation, leaving a residue which is mixed 30 beef extract, 125 parts of commercial peptone, 3 parts with 2250 parts of benzene and 1750 parts of hexane. of silicone antifoaming agent, and 30,000 parts of water. The organic phase is separated (there being no crystalline Tank and medium are sterilized by heating to tempera solids present), and stripped of solvent by vacuum dis tures of the order of 110-120' and then cooled to about tillation. The residue thus obtained is taken up in 7500 25, whereupon an inoculant prepared by adding a cul parts of chloroform. The chloroform solution is ex 35 ture of Corynebaterium simplex A.T.C.C. No. 6946 to tracted with aqueous 5% potassium hydroxide. Upon a sterile medium consisting of 6 parts of commercial acidification, a solid precipitates which, filtered off, washed beef extract, 10 parts of commercial peptone, and 2000 with methanol, and dried in air, melts in the range of parts of water and incubating the resultant mixture 72 210-234. The mixture thus isolated consists largely of hours at 25 is introduced. The medium is maintained 40 at about 25 for 24 hours, during which time a stream estrone and estradiol, the latter being a mixture of the of sterile air is passed through at the rate of about 5000 17-epimers. parts by volume per minute, and the developing culture Example 44 is agitated to produce submerged growth. A solution of 10 parts of 22a-spirost-4-en-3-one in 250 parts of acetone A mixture of 14 parts of lithium wire cut in 4' is then introduced, and agitation with aeration at about lengths, 160 parts of biphenyl, 85 parts of diphenylmeth 45 25 is thereupon resumed for 24 hours. The mixture ane, and 1800 parts of tetrahydrofuran is heated to boiling thus obtained is extracted with dichloromethane. The under reflux with vigorous agitation in a nitrogen atmos extract is dried over anhydrous sodium sulfate and stripped phere while a deep green color develops. Boiling under of solvent by distillation. The residue is 22a-spirosta reflux with vigorous agitation and protected by nitrogen 1,4-dien-3-one. is continued while a solution of 143 parts of 176-hydroxy 50 (B) A mixture of 33 parts of a 30% dispersion of androsta-1,4-dien-3-one in 630 parts of tetrahydrofuran lithium in paraffin, 154 parts of biphenyl, 84 parts of is added at a rate such that the green color is not dis diphenylmethane, and 900 parts of tetrahydrofuran is charged, approximately 40 minutes being required. A heated to boiling under reflux with vigorous agitation in solid precipitates in process. The reactants are consecu a nitrogen atmosphere while the characteristic deep color tively mixed under nitrogen with 400 parts of methanol, 55 develops. Boiling under reflux with vigorous agitation 500 parts of water, and 300 parts of concentrated hydro and protected by nitrogen is continued while a solution chloric acid. The resultant mixture is warmed at 60 of 205 parts of 22a-spirosta-1,4-dien-3-one in 900 parts for 30 minutes, then stripped of solvents by vacuum distill of warm tetrahydrofuran is introduced during 4 hour, lation. The residue is consecutively mixed with 900 parts and for 15 minutes thereafter. Then, 320 parts of metha of benzene and 700 parts of hexane. Insoluble 176 60 nol and 500 parts of water are consecutively introduced, estradiol is filtered off, washed on the filter with methanol, whereupon the mixture is cooled to room temperature and and dried in air. Extraction of the combined filtrate acidified with 1000 parts of 10% acetic acid. Organic and wash with aqueous potassium hydroxide, followed by Solvents are removed by vacuum distillation, and the resi acidification of the extract, affords additional product. 65 due is triturated with ether. In soluble solids are 19-nor Example 45 22a-spirosa-1,3,5 (10)-trien-3-ol which, isolated by filtra tion, washed on the filter with ether and water, and dried (A) To a solution of 143 parts of 176-hydroxyandrosta in air, melts at 236-242. 1,4-dien-3-one in 1340 parts of dichloromethane is added 180 parts of dihydropyran and 1 part of p-toluenesulfonic 70 Example 48 acid. The resultant mixture is warmed to 35, where A mixture of 10 parts of potassium, 50 parts of naph upon it is allowed to stand overnight, then washed with thalene, and 225 parts of benzene is heated at the boiling water, dried over potassium carbonate, and stripped of point under reflux with vigorous agitation in a nitrogen solvent by vacuum distillation. The residue is 176-(2'- atmosphere until a blue color develops. Boiling under tetrahydropyranyloxy)androsta-1,4-dien-3-one. 75 reflux with vigorous agitation and protected by nitrogen y

3,274,182 2. is continued while a solution of 25 parts of androsta-1,4- tively, called for in the preceding Example 50 affords, by diene-3,17-dione 17-ethylene ketal in 90 parts of benzene the procedure there detailed, estrone of comparable purity is added at a rate such that the blue color is never dis in somewhat better yield. The product melts at 250 charged (20 minutes required), and for 30 minutes there 255. after. Then, 40 parts of methanol, 200 parts of water, Example 52 and 120 parts of concentrated hydrochloric acid are con A mixture of 64 parts of a 50% dispersion of lithium secutively mixed in under nitrogen. The resultant mix in paraffin, 470 parts of biphenyl, 256 parts of diphenyl ture is warmed at around 60° for 30 minutes, following methane, and 2700 parts of tetrahydrofuran is heated to which the benzene phase is separated, washed with water, boiling under nitrogen with vigorous agitation while a and extracted with aqueous 5% potassium hydroxide. IO deep green color develops. Boiling under reflux with Upon acidification of the alkaline extract, estrone pre vigorous agitation and protected by nitrogen is continued cipitates. while a solution of 500 parts of androsta - 14 - diene Example 49 3,17-dione 17 - ethylene ketal in approximately 1500 parts of Warm benzene is added at a rate such that the A mixture of 35 parts of sodium, 41 parts of naphtha 5 characteristic color is not discharged (20 minutes re lene, 26 parts of diphenylmethane, and 300 parts of spe quired), and for 15 minutes thereafter. Then, 800 parts cially purified dioxane is heated at the boiling point under of methanol, 1000 parts of water, and 840 parts of con reflux with vigorous agitation in a nitrogen atmosphere centrated hydrochloric acid are consecutively introduced until a deep blue-green color develops. N.B. 'specially under nitrogen. The resultant mixture is warmed at 60 purified” as used in this and succeeding examples denotes 20 for 30 minutes, following which organic solvents are re solvent which is preliminarily distilled from a mixture moved by distillation. The residue is mixed with 1125 of activated alumina and anhydrous sodium hydroxide, parts of benzene and 875 parts of hexane. This mixture then mixed at room temperature with potassium until is chilled and the estrone which separates collected on a any reaction. Subsides, and thereupon heated to boiling or filter, washed thereon with methanol, and dried in air. 150 (whichever is lower) with vigorous agitation for 25 Extraction of the combined filtrate and wash with aqueous 30 minutes. At this point, naphthalene is introduced; potassium hydroxide, followed by acidification of the ex and agitation is continued until the characteristic green tract, affords additional product. The estrone thus pre adduct color develops, whereupon the solvent is distilled. pared melts at 245-256. Boiling under reflux with vigorous agitation and pro tected by nitrogen is continued while a solution of 50 30 Example 53 parts of androsta - 1,4-diene - 3,17-dione 17 - ethylene A mixture of 64 parts of a 50% dispersion of lithium ketal in 200 parts of dioxane is introduced at a rate such in paraffin, 470 parts of biphenyl, 256 parts of diphenyl that the blue-green color is not discharged, approximately methane, and 2700 parts of methyl tetrahydrofurfuryl 1 hour being required. Then, 40 parts of methanol, 200 ether is heated to 65 under nitrogen with vigorous agi parts of water, and 180 parts of concentrated hydro 35 tation (the characteristic deep blue-green color forms at chloric acid are consecutively mixed in under nitrogen. once) and maintained thus while a solution of 500 parts The resultant mixture is warmed at around 60' for 30 of androsta - 1,4-diene - 3,17-dione 17 - ethylene ketal minutes, following which it is stripped of solvent by in approximately 1200 parts of warm benzene is added vacuum distillation. The residue is mixed with 135 parts at a rate Such that the color is not discharged (25 min of benzene, and the mixture is allowed to stand while 40 lutes required), and for 15 minutes thereafter. There separation of estrone continues. The estrone is isolated upon, 800 parts of methanol, 1000 parts of water, and 960 by filtration. Extraction of the filtrate with aqueous potas parts of concentrated hydrochloric acid are consecutively sium hydroxide, followed by acidification of the extract, mixed in under nitrogen; and the resultant mixture is affords additional product. Warmed at 50 for 30 minutes. The mixture is then 45 stripped of Solvent by vacuum distillation, and the resi Example 50 due is consecutively mixed with 1125 parts of benzene A mixture of 80 parts of lithium wire cut in small and 875 parts of hexane. The estrone which has sepa pieces, 940 parts of technical dimethylnaphthalene, 520 rated is filtered from the chilled mixture, washed with parts of diphenylmethane, and 5400 parts of tetrahydro 1:1 benzene-hexane and then with methanol, and finally furan is heated to boiling under reflux with vigorous agi 50 dried in warm air. It melts at 255-259. Extraction of tation in a nitrogen atmosphere while the characteristic the combined filtrate and washes with aqueous potassium color develops. Boiling under reflux with vigorous agi hydroxide, followed by acidification of the extract, affords tation and protected by nitrogen is continued while a additional product. solution of 1000 parts of androsta - 14 - diene - 3,17 Example 54 dione 17-ethylene ketal in approximately 2900 parts of 55 warm tetrahydrofuran is added over 45 minutes, and for A mixture of 25 parts of a 40% dispersion of lith 15 minutes thereafter. Then, 800 parts of methanol, 2000 ium in paraffin, 50 parts of biphenyl, 26 parts of di parts of water, and 1200 parts of concentrated hydro phenylmethane, and 285 parts of specially purified (see chloric acid are consecutively mixed in under nitrogen. Example 49) bis(2-methoxyethyl) ether (“diglyme”) is The resultant mixture is warmed at 60 for 30 minutes, 60 heated at 120° with vigorous agitation under nitrogen following which it is stripped of solvent by vacuum dis until a green color develops, and maintained thus while tillation. The residue is suspended in 2250 parts of ben a Solution of 25 parts of androsta-1,4-diene-3,17-dione Zene, whereupon 1750 parts of hexane is mixed in and 17-ethylene ketal in 245 parts of bis(2-methoxyethyl) the mixture allowed to stand briefly while estrone sepa ether is added during 90 minutes. Then, 40 parts of rates. The estrone is filtered off and consecutively washed 65 methanol, 200 parts of water, and 150 parts of con with 1:1 benzene-hexane, methanol, water, and methanol. centrated hydrochloric acid are consecutively mixed in Dried in warm air, it melts at 249-256. Extraction of under nitrogen. The resultant mixture is warmed at the combined filtrate and washes with aqueous potassium 60 for 30 minutes, following which it is stripped of hydroxide, followed by acidification of the extract, affords Solvent by vacuum distillation. The residue is parti additional product. 70 tioned between benzene and aqueous 5% potassium hy Example 51 droxide. Upon acidification of the potassium hydroxide phase, estrone precipitates. Substitution of 95 parts of lithium and 862 parts of 26 - dimethylnaphthalene for the 80 parts of lithium Example 55 and 940 parts of technical dimethylnaphthalene, respec 75 A mixture of 35 parts of potassium, 95 parts of bi pr

3,274,182 23 24. phenyl, 52 parts of diphenylmethane, and 540 parts parts of tetrahydrofuran, 70 parts of ether, 1 part of of tetrahydrofuran is heated to boiling under reflux with Water, approximately 1 part of aqueous 20% sodium. vigorous agitation in a nitrogen atmosphere while a deep hydroxide, and 5 parts of water. The mixture thus ob blue color develops. Boiling under reflux with vigor tained is allowed to stand 10 minutes, whereupon pre ous agitation and protected by nitrogen is continued 5 cipitated solids are filtered off and washed with chloro while a solution of 100 parts of androsta-1,4-diene-3,17 form. The filtrate is combined with the chloroform dione 17-ethylene ketal in approximately 290 parts of wash, and the resultant liquors dried over magnesium sul tetrahydrofuran is introduced at a rate such that the fate and stripped of solvent by vacuum distillation. The blue color is continuously maintained, approximately 15 residue, triturated with ether, affords colorless crystals minutes being required. To the mixture is then con of 11g-hydroxyandrosta-1,4-diene-3,17-dione 17-ethylene secutively added 80 parts of methanol, 150 parts of O ketal melting in the range, 175-185. water, and 120 parts of concentrated hydrochloric acid (C) To a mixture of approximately 42 parts of a 30% with vigorous agitation under nitrogen. The resultant dispersion of lithium in paraffin, 125 parts of biphenyl, mixture is heated at 60° for 30 minutes, following which approximately 69 parts of diphenylmethane, and 1080 it is stripped of solvent by vacuum distillation. The 5 parts of tetrahydrofuran is added, with vigorous agitation residue is suspended in 180 parts of benzene, whereupon at the boiling point under reflux during 35 minutes, a hot 140 parts of hexane is mixed in and the mixture allowed solution of 100 parts of 116-hydroxyandrosta-1,4-diene-3, to stand briefly while estrone precipitates. The estrone, 17-dione 17-ethylene ketal in 765 parts of tetrahydrofuran. isolated by filtration, washed with methanol, and dried The resultant mixture is maintained at the boiling point in warm air, melts at 248-253 (corr.). Extraction of 20 under reflux for 10 minutes, whereupon 28 parts of metha the combined filtrate and wash with aqueous potassium nol and 80 parts of water are consecutively and cautiously hydroxide and acidification of this extract affords addi introduced. A further 400 parts of water is then added, foll tional product. lowing which tetrahydrofuran is removed by vacuum dis Example 56 tillation. The residue is cooled to room temperature and (A) A mixture of 1 part of androsta-1,4-diene-3,17 diluted with approximately 700 parts of a 3:1 (by volume) dione, 766 parts of trimethyl orthoformate, 10 parts of mixture of benzene and hexane. The aqueous phase is p-toluenesulfonic acid, and 400 parts of methanol is thereupon separated and the organic phase washed re heated at the boiling point under reflux with agitation peatedly with 200-part portions of aqueous 5% potassium for 30 minutes, then cooled to room temperature and hydroxide. Aqueous phase and washings are then com diluted with approximately 400 parts of 10% metha 30 bined, washed twice with 200-part portions of hexane, and nolic potassium hydroxide. The resultant solution is slowly added with vigorous agitation to a slurry of 200 allowed to evaporate until crystallization begins, at which parts of acetic acid, 200 parts of water, and 200 parts of point evaporation is halted and crystallization allowed to ice, the temperature throughout being maintained below proceed to completion. The crystals are filtered off and 10. The solid precipitate thrown down is isolated by washed with 800 parts of cold methanol. The product 35 filtration, washed with water, and dried in vacuo to afford thus isolated is androsta-1,4-diene-3,17-dione 17,17-di 3,11f8-dihydroxyestra - 1,3,5(10)-trien-17-one 17-ethylene methyl ketal. ketal which, recrystallized from a mixture of acetone and (B) A mixture of 25 parts of a 30% dispersion of petroleum ether, melts at 186-191. lithium in paraffin, 95 parts of biphenyl, 52 parts of (D) To a solution of 32 parts of 3,116-dihydroxy diphenylmethane, and 540 parts of tetrahydrofuran is 40 estra-1,3,5(10)-trien-17-one 17-ethylene ketal in approxi heated to boiling under reflux with vigorous agitation mately 350 parts of a hot 3:1 (by volume) mixture of in a nitrogen atmosphere while a dark green color de methanol and water is added approximately 4 parts of velops. Boiling under reflux with vigorous agitation 15% hydrochloric acid. The resultant solution is heated and protected by nitrogen is continued while a Solution at around 90 for a few moments while crystallization of 96 parts of androsta-1,4-diene-3,17-dione 17,17-di 45 ensues. The resultant mixture is allowed to stand at room methyl ketal in 270 parts of warm tetrahydrofuran is temperatures for 1 hour, whereupon it is cooled to around introduced at a rate such that the green color is always 5. Insoluble solids are filtered of, washed with water, present, approximately 20 minutes being required. Con and dried in air to afford 3,11,3-dihydroxyestra-1,3,5(10) secutive introduction of 80 parts of methanol, 100 parts trien-17-one melting in the range 240-252. of water, and approximately 180 parts of concentrated 50 What is claimed is: hydrochloric acid under nitrogen, and subsequent Strip 1. In a process for converting a steroidal 19-methyl-1, ping of solvent by vacuum distillation, affords a residue and dried in air to afford 3,116-dihydroxyestra-1,3,5 (10)- which is mixed with 180 parts of benzene and 130 parts triene, the step which consists of contacting a member of of hexane. The crystalline product which forms is fil the group consisting of compounds of the formulas

tered off and washed with 80 parts of methanol. The 55 estrone thus isolated is obtained in excellent yield. It melts at approximately 246-247 (corr.). Example 57 (A) A mixture of 23 parts of androsta-1,4-diene-3, 60 11,17-trione, approximately 17 parts of 1,2-ethanediol, 2 parts of p-toluenesulfonic acid monohydrate, and 1800 parts of benzene is heated at the boiling point under reflux with agitation for 2 hours, water being removed as formed. The reaction mixture is then cooled, con 65 secutively washed with aqueous Sodium carbonate and water, dried over magnesium sulfate, and freed of Sol vent by vacuum distillation. Trituration of the resi due with ether affords androsta-1,4-diene-3,11,17-trione 17-ethylene ketal melting at 213-215. - 70 (B) A solution of 5 parts of androsta-1,4-diene-3,11, 17-trione 17-ethylene ketal and 10 parts of lithium tri tert-butoxyaluminum hydride in 180 parts of tetrahy drofuran is stirred for 18 hours at room temperatures. To the resultant solution is consecutively added 180 75 3,274,182 25 26 androsta-1,4-diene-3,17-dione 17-17-dimethyl ketal, 116 a member of the group consisting of androsta-1,4-diene hydroxyandrosta-1,4-diene - 3,17-dione 17,17-dimethyl 3,17-dione 17,17-dimethyl ketal, 116-hydroxyandrosta-1,4- ketal, and 22a-spirosta-1,4-dien-3-one with a member of diene-3,17-dione 17,17-dimethyl ketal, and ketals of the the group consisting of alkali metals and mixtures thereof formula in the presence of a solvent and a radical anion precursor, 5 said solvent being a member of the group consisting of Alk / N lower aliphatic ethers, fully alkylated polyhydric alcohols, O O acetals, cyclic ethers, tertiary amines, and benzene, said radical anion precursor being a member of the group con H3C V sisting of biphenyl, naphthalene, methylnaphthalene, di 10 R methylnaphthalene, phenanthrene, terphenyl, anthracene, HC acenaphthene, fluoranthene, dibenzofuran, and benzophe none, Alk in the first formula being an alkylene radial con taining more than 1 and fewer than 6 carbon atoms and R therein being a member of the group consisting of hydro 5 gen and hydroxyl and, in the second formula, R being defined as before, R' being a member of the group consist in an inert solvent, Alk in the formula being an alkylene ing of hydrogen and a tetrahydropyranyl radical, and R' radical containing more than 1 and fewer than 6 carbon being a member of the group consisting of hydrogen and a atoms and R therein being a member of the group consist lower alkyl radical containing fewer than 3 carbon atoms. 20 ing of hydrogen and hydroxyl. 2. In a process for converting a steroidal 19-methyl 4. In a process for converting an androsta-1,4-dien-3- 1,4-dien-3-one to the corresponding 19-nor-3-oxy-1,3,5- one to the corresponding 3-oxyestra-1,3,5(10)-triene, the (10)-triene, the step which consists of contacting a mem steps which consist of (1) mixing an alkali metal with a ber of the group consisting of compounds of the formulas radical anion precursor selected from the group consisting 25 of biphenyl, naphthalene, methylnaphthalene, phenan Alk threne, and terephenyl in the presence of (a) a solvent / N selected from the group consisting of lower aliphatic ethers, O O fully alkylated polyhydric alcohols, acetals, cyclic ethers, H3C tertiary amines, and benzene and (b) a scavenger selected R from the group consisting of diphenylmethane and methyl 30 naphthalene and (2) mixing therewith a member of the HC group consisting of androsta-1,4-diene-3,17-dione 17,17 4N/N/ dimethyl ketal, 11.f3-hydroxyandrosta-1,4-diene-3,17-dione 17,17-dimethyl ketal, and ketals of the formula o 35 Né Alk / N O O OR

androsta-1,4-diene-3,17-dione 17,17-dimenthyl ketal, 116 45 in an inert solvent, Alk in the formula being an alkylene hydroxyandrosta-1,4-diene-3,17-dione 17,17-dimenthyl radical containing more than 1 and fewer than 6 carbon ketal, and 22a-spirosta-1,4-dien-3-one with a member of atoms and R therein being a member of the group consist the group consisting of alkali metals and mixtures there ing of hydrogen and hydroxyl. of in the presence of (a) a radical anion precursor selected 5. In a process for converting an androsta-1,4-dien-3- from the group consisting of biphenyl, naphthalene, meth 50 one to the corresponding 3-oxyestra-1,3,5(10)-triene, the ylnaphthalene, dimethylnaphthalene, phenanthrene, ter steps which consist of (1) mixing an alkali metal with a phenyl, anthracene, acenaphthene, fluoranthene, dibenzo radical anion precursor selected from the group consisting furan, and benzopenone, (b) a scavenger selected from of biphenyl, naphthalene, methylnaphthalene, phenan the group consisting of diphenylmethane and methylnaph threne, and terphenyl in the presence of a solvent selected thalene, and (c) a solvent selected from the group con 55 from the group consisting of lower aliphatic ethers, fully sisting of lower aliphatic ethers, fully alkylated polyhydric alkylated polyhydric alcohols, acetals, cyclic ethers, terti alcohols, acetals, cyclic ethers, tertiary amines, and benzene ary amines, and benzene and (2) mixing therewith a solu Alk in the first formula being an alkylene radical contain tion of (a) a member of the group consisting of androsta ing more than 1 and fewer than 6 carbon atoms and R 1,4-diene-3,17-dione 17,17-dimethyl ketal, 11B-hydroxy therein being a member of the group consisting of hydro 60 androsta - 1,4-diene-3,17-dione-17,17-dimethyl ketal, and gen and hydroxyl and, in the second formula, R being de ketals of the formula fined as before, R' being a member of the group consisting of hydrogen and a tetrahydropyranyl radical, and R' being a member of the group consisting of hydrogen and a lower ?', alkyl radical containing fewer than 3 carbon atoms. 65 3. In a process for converting an androsta-1,4-dien-3- R V one to the corresponding 3-oxyestra-1,3,4(10)-triene, the steps which consist of (1) mixing an alkali metal with a radical anion precursor selected from the group consist ing of biphenyl, naphthalene, methylnaphthalene, phen 70 O) anthrene, and terphenyl in the presence of a solvent Select ed from the group consisting of lower aliphatic ethers, ol fully alkylated polyhydric alcohols, acetals, cyclic ethers, wherein Alk represents an alkylene radical containing tertiary amines, and benzene and (2) mixing therewith 75 more than 1 and fewer than 6 carbon atoms and R repre pr

3,274,182 27 28 sents a member of the group consisting of hydrogen and AIk hydroxyl and (b) a scavenger selected from the group / N consisting of diphenylmethane and methylnaphthalene in O O an inert solvent. H3C 6. In a process for converting an androsta-1,4-dien-3- R-/ one to the corresponding 3-oxyestra-1,3,5(10)-triene, the step which consists of heating a member of the group con H3C sisting of androsta-1,4-diene-3,17-dione 17,17-dimethyl ketal, 116-hydroxyandrosta-1,4-diene-3,17-dione 17,17-di r / methyl ketal, and ketals of the formula 10 O= N/ Alk wherein Alk represents an alkylene radical containing / N more than 1 and fewer than 6 carbon atoms and R rep O O resents a member of the group consisting of hydrogen H3C and hydroxyl, (b) a scavenger selected from the group consisting of diphenylmethane and methylnaphthalene, and (c) a solvent selected as before. 9. In a process for converting an androsta-1,4-dien-3- one to the corresponding 3-oxyestra-1,3,5(10)-triene, the 20 steps which consist of (1) mixing an alkali metal with a radical anion precursor selected from the group con sisting of biphenyl, naphthalene, methylnaphthalene, phenanthrene, and terphenyl in the presence of (a) a with an ankali metal in the presence of (a) a radical anion scavenger selected from the group consisting of diphenyl precursor selected from the group consisting of biphenyl, 25 methane and methylnaphthalene and (b) a boiling solvent naphthalene, methylnaphthalene, phenanthrene, and ter selected from the group consisting of tetrahydrofuran phenyl and (b) a solvent selected from the group con and 1,2-dimethoxyethane and (2) mixing therewith at sisting of tetrahydrofuran and 1,2-dimethoxyethane, Alk the boiling point of the aforesaid solvent (a) a member in the formula being an alkylene radical containing more 30 of the group consisting of androsta-1,4-diene-3,17-dione than 1 and fewer than 6 carbon atoms and R therein being 17,17-dimethyl ketal, 11(3-hydroxyandrosta - 1,4-diene a member of the group consisting of hydrogen and hy 3,17-dione 17,17-dimethyl ketal, and ketals of the for droxyl. mula 7. In a process for converting an androsta-1,4-dien-3- Alk one to the corresponding 3-oxyestra-1,3,5(10)-triene, the 35 step which consists of heating a member of the group 6 o consisting of androsta-1,4-diene - 3,17-dione 17,17-di HC methyl ketal, 116-hydroxyandrosta - 1,4-diene-3,17-dione R 17,17-dimethyl ketal, and ketals of the formula HC 4) / Ak. 6 o H,\/ Os wherein Alk represents an alkylene radical containing R 45 more than 1 and fewer than 6 carbon atoms and R repre Es C sents a member of the group consisting of hydrogen and / hydroxyl and (b) a solvent selected as before. 10. In a process for converting an androsta-1,4-dien-3- one to the corresponding 3-oxyestra-1,3,5(10)-triene, the O-2 50 steps which consist of (1) mixing an alkali metal with a radical anion precursor selected from the group consist with an alkali metal in the presence of (a) a radical ing of biphenyl, naphthalene, methylnapthalene, phenan anion precursor selected from the group consisting of threne, and terphenyl in the presence of a boiling solvent biphenyl, naphthalene, methylnaphthalene, phenanthrene, 55 Selected from the group cosisting of tetrahydrofuran and and terphenyl, (b) a scavenger selected from the group 1,2-dimethoxyethane and (2) mixing with an excess of consisting of diphenylmethane and methylnaphthalene, the resultant radical anion at the boiling point of the and (c) a solvent selected from the group consisting of aforesaid solvent (a) a member of the group consisting tetrahydrofuran and 1,2-dimethoxyethane, Alk in the of androsta - 1,4-diene - 3,17-dione 17,17-dimethyl ketal, formula being an alkylene radical containing more than 60 11.f3-hydroxyandrosta - 1,4-diene - 3,17-dione 17,17-di 1 and fewer than 6 carbon atoms and R therein being methyl ketal, and ketals of the formula a member of the group consisting of hydrogen and hy droxyl. 8. In a process for converting an androsta-1,4-dien-3- one to the corresponding 3-oxyestra - 1,3,5 (10)-triene, 65 the steps which consist of (1) mixing an alkali metal with a radical anion precursor selected from the group consisting of biphenyl, naphthalene, methylnaphthalene, phenanthrene, and terphenyl in the presence of a boiling solvent Selected from the group consisting of tetrahydro 70. furan and 1,2-dimethoxyethane and (2) mixing therewith at the boiling point of the solvent (a) a member of the group consisting of androsta-1,4-diene-3,17-dione 17, 17 dimethyl ketal, 11 (3-hydroxyandrosta-1,4-diene-3,17-dione wherein Alk represents an alkylene radical containing 17,17-dimethyl ketal, and ketals of the formula 75 more than 1 and fewer than 6 carbon atoms and R repre

y

3,274,182 29 sents a member of the group consisting of hydrogen and 15. The process of converting androsta-1,4-diene-3,17 hydroxyl (b) a scavenger selected from the group con dione 17-ethylene ketal to the corresponding 3-oxyestra sisting of diphenylmethane and methylnaphthalene, and 1,3,5 (10)-triene which comprises mixing a solution of (c) a solvent selected as before. the ketal in tetrahydrofuran under a nitrogen atmosphere 1. The process of converting an androsta-1,4-dien-3- with a boiling mixture of diphenylmethane and a continu one to the corresponding 3-oxyestra-1,3,5 (10)-triene ous excess of the radical anion solution obtained by mix which comprises mixing a solution of a member of the ing a dispersion of lithium in paraffin with naphthalene group consisting of androsta-1,4-diene-3,17-dione 17, 17 in boiling tetrahydrofuran under nitrogen. dimethyl ketal, 116-hydroxyandrosta-1,4-diene-3,17-dione 16. The process of converting androsta-1,4-diene-3,17 17,17-dimethyl ketal, and ketals of the formula O dione 17-ethylene ketal to the corresponding 3-oxyestra Alk 1,3,5 (10)-triene which comprises mixing a solution of / N the ketal in tetrahydrofuran under a nitrogen atmosphere O O With a boiling mixture of diphenylmethane and a continu HscV ous excess of the radical anion solution obtained by mix 5 ing a dispersion of lithium in paraffin with phenanthrene R in boiling tetrahydrofuran under nitrogen. H3C 17. The process of converting androsta-1,4-diene-3,17 dione 17-ethylene ketal to the corresponding 3-oxyestra 1,3,5 (10)-triene which comprises mixing a solution of 20 the ketal in tetrahydrofuran under a nitrogen atmosphere with a boiling mixture of diphenylmethane and a con in an inert solvent with a boiling solution of diphenyl tinuous excess of the radical anion solution obtained by methane and the radical anion obtained by mixing lithium mixing a dispersion of lithium in paraffin with terphenyl with biphenyl in the presence of boiling tetrahydrofuran, in boiling tetrahydrofuran under nitrogen. 25 18. The process of converting androsta-1,4-diene-3,17 Alk in the formula being an alkylene radical containing dione 17,17-dimethyl ketal to the corresponding 3-ox more than 1 and fewer than 6 carbon atoms and R being yestra-1,3,5 (10)-triene which comprises mixing a solu a member of the group consisting of hydrogen and tion of the ketal in tetrahydrofuran under a nitrogen hydroxyl. atmosphere with a boiling mixture of diphenylmethane 12. The process of converting androsta-1,4-diene-3,17 30 and a continuous excess of the radical anion solution ob dione 17-ethylene ketal to the corresponding 3-oxyestra tained by mixing a dispersion of lithium in paraffin with 1,3,5 (10)-triene which comprises mixing a solution of biphenyl in boiling tetrahydrofuran under nitrogen. the ketal in tetrahydrofuran under a nitrogen atmos 19. The process of converting a member of the group phere with a boiling mixture of diphenylmethane and consisting of 17,3-hydroxyandrosta-1,4-dien-3-one and its a continuous excess of the radical anion solution obtained 35 17-tetrahydropyranyl ether to the corresponding 3 by mixing a dispersion of lithium in paraffin with bi OXyeStra-1,3,5(10)-triene which comprises heating a solu phenyl in boiling tetrahydrofuran under nitrogen. tion of Said member in an inert solvent under nitrogen 13. The process of converting androsta-1,4-diene-3,17 With a mixture of diphenylmethane and a continuous dione 17-ethylene ketal to the corresponding 3-oxyestra excess of the radical anion solution obtained by heating 1,3,5 (10)-triene which comprises mixing a solution of 40 lithium with biphenyl in the presence of tetrahydro the ketal in tetrahydrofuran under a nitrogen atmos furan under nitrogen. phere with a boiling mixture of methylnaphthalene and 20. The process of converting 22a-spirosta-1,4-dien a continuous excess of the radical anion solution obtained 3-one to the corresponding 19-nor-3-oxy-22a-spirosta by mixing a dispersion of lithium in paraffin with bi 1,3,5 (10)-triene which comprises heating a solution of phenyl in boiling tetrahydrofuran under nitrogen. 45 Said 220-Spirosta-1,4-dien-3-one in an inert solvent under 14. The process of converting androsta-1,4-diene-3,17 nitrogen with a mixture of diphenylmethane and a con dione 17-ethylene ketal to the corresponding 3-oxyestra tinuous excess of the radical anion solution obtained by 1,3,5 (10)-triene which comprises mixing a solution of heating lithium with biphenyl in the presence of tetra the ketal in tetrahydrofuran under a nitrogen atmosphere hydrofuran under nitrogen. with a continuous excess of the radical anion solution ob tained by mixing a dispersion of lithium in paraffin with 50 methylnaphthalene in boiling tetrahydrofuran under No references cited. nitrogen. LEWIS GOTTS, Primary Examiner. UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 274, 182 September 20, 1966 Hugh L. Dryden, Jr., et al. It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below. Column l, lines 12 and 13, for "April 8, 1959' read -- March 4, 1963 - -; column 2, line 24, strike out "The 3-oxyestra 1, 3, 5 (10) - trienes produced by the process'; column 3, line 66, for 'constiutes' read - - constitutes --; column 5, line 35, for "containnig" read -- containing -- ; line 52, for "conductive" read -- conducive -- ; column 18 line 2, strike out 'during the ketal addition, and reappears only slowly. By" and insert the same after "reaction", in line 24, same column 18; line 19, for "at" read -- to --; column 20, line 65, for "In soluble" read -- Insoluble -- ; line 66, for "spirosa' read -- spirosta - -; column 24, line 52, strike out "and dried in air to afford 3, 11 6-dihydroxyes tra" and insert instead -- 4-dien-3-one to the corresponding 19-nor-3-oxy --; column 25, line 46, for "dimenthyl" read -- dimethyl -- ; line 68, for "1, 3, 4 (10) -" read -- 1, 3, 5 (10) - - -; column 27, line 25, for "ankali' read -- alkali - - , Signed and sealed this 29th day of August 1967. i

(SEAL) Attest: ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents