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‘rates 3,945,032 I , Patented July 17, 119,62 ‘ ' l. Robinson, Serial No. 7,107, ?led February 8, 1960. .- Ac cording to this process, androsterone is converted ‘to the intermediary 16-hydroxymethylene (l6-formyl) or 16 ethoxalyl androsterone by methods well known in the art; 3,045,032 FLUQRHNATED ANDRBSTANEg Cecil H. Robinson, Qedar Grove, and Eugene P. Oliveto, Glen Ridge, N..l'., assignors to Schering Corporation, , We prefer to formylate'the activated C-16 position by reacting androsterone with ethyl formate and sodium ‘ methoxide or sodium hydride utilizing as solvent, benzene or tetrahydrofuran or mixtures thereof. The l6-formyl Bloom?eld, N.J., a corporation of New Jersey No Drawing. Filed Feb. 8, 1960, Ser. No. 7,116 6 Claims. '(Cl. 26tl--397.4) This invention relates to novel, therapeutically active derivative thereby obtained apparently exists in two tau steroids of the androstane series. More speci?cally, this 10 tomeric forms, namely formyl and hydroxymethylene. invention relates to 16,16-di?uoroandrostanes which are saturated in the A-ring and have an-oxygen function at 0-17. In particular, our invention encompasses 16,16 di?uoro derivatives of androsterones and of androstane diol-3a,l7B as well as the l6,16—di?uoro-l7u-alkyl and 15 l6,l6-di?uoro-l7a-alkynyl derivatives of the aforemen tioned androstanediol, including intermediates in the prep Alternatively, the l6-ethoxalyl derivative of androsterone is prepared according to procedures similar to those for preparing the 16-hydroxymethylene derivatives. by using ethyl oxalate as reagent instead of ethyl formate. By reacting the intermediary l6-hydroxymethylene androsterone or l6-ethoxalylandrosteronewith perchloryl ?uoride in the presence of alkoxide preferably potassium t-butoxide in t-butanol solvent, there is obtained 16,16 aration thereof. - Our novel l6,léédi?uoroandrostaneshave the following ‘ di?uoroandrosterone, a novel compound of our inven- ' general formula: tion. Y ona z i . > The compound 16,16-di?uoroandrosterone, prepared as described above, may be transformed to the 17a-1ower alkynyl-l7?-hydroxy or 17u-lOW6I' alkyl-l7/3-hydroxy an on, F alogs by known methods. 25 For example, 16,16-di?uoro- I androsterone is readily transformed to l6,l6~di?uoro— l7a-methylandrostane-3a,17?-diol by the well’ known Grignard reaction utilizing methyl magnesium iodide, .or to the corresponding l7ot-ethinyl derivative by means of sodium or potassium acetylide. The l7~hyclroxy com 30 pound,_i.e. l6,16=di?uoroandrostane-3a,17,8-diol is con~ veniently obtained from the l7-keto analog by reduction wherein Z is a member of the group consisting of O, 30- I V with lithium aluminum hydride, sodium borohydride, plat (H, 50R’), (Ct-IOWBI' alkyl, 30R’) and (oc-10W61‘ alkynyl, inum and hydrogen, and the like. ?OR’) wherein R andR’ are members of the group con By substituting suitable reagents in the aforementioned sisting of H and an acyl radical of a hydrocarbon car 35 reactions, such as ethyl magnesium bromide instead of’ boxylic acid containing up to eight carbon atoms. R and R’ may be alike or different. methyl magnesium iodide in the Grignard reaction on 16,16-di?uoroandrosterone, there are obtained higher alkyl homologs at C-17 for example, 16,16-di?uoro-‘17a , Our invention therefore includes novel compounds such as 16,16-di?u0roandrostane-3m-ol-l7-one (16,16-diiluoro androsterone) , 16,16-di?uoroandrostane-3a,17,6-diol ( 16,— 40 16 - di?uoroandrostanediol - 30;,175), l6,16_- di?uoro 17cc - methylandrostane - 304,176 - diol, 16,1-6 - di?uoro 17a-ethinylandrostane-3u,17,8-diol, and the lower alka noate esters thereof. By lower alkyl is contemplated hydrocarbon radicals having up .to four carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl and the like. By lower alkynyl is contemplated hydrocarbon radicals ethylandrosterone-l7,8-01. In preparing higher C~l7 homologs of 16,l6-di?uoro-17a~ethinylandrosterone-17p ‘ ‘ 01, it is preferred to alkylate the active hydrogen on the ethinyl moiety by means of lithium and methyl iodide, for example, to obtain 1‘6,l6-di?uoro-17a-(1’-propynyl)-an drostane-3a,l7/S-diol. When ethyl iodide and lithium are 45 reacted with the aforementioned l7a-ethinyl derivatives 2 there is ‘obtained the corresponding l7ot-butynyl com pound, , i.e. 16,16-d1'?uor0-17a-(l'-butynyl)-androstane~ having up to four carbon atoms possessing a triple-bond Alternatively, our 16,16-di?uoroandrostanes maybe stemming from the carbon attached to the l7-carbon of 50 prepared from l6,l6~di?uoro-5-androstenes. For exam the steroid nucleus. Included in this groupv are radicals ple, l6,l6-di?uoro~5-androstene-3B-ol-l7-one prepared as such as ethinyl, l-propynyl and l-butynyl. described in copending application, Serial No. 7,107, ?led The acyl radicals of hydrocarbon carboxylic acids con February 8, 1960, from l6-hydroxy-methylene-S-andros taining up to eight carbon atoms are preferably radicals of tone-3 ?-ol- l 7-one and perchloryl ?uoride upon hydrogena-, lower alkanoic acids such as acetic, propionic, valer-ic, 55 tion in ethyl acetate utilizing'platinum oxide as catalyst butyric, caproic acid and the like. , yields l6,l6-di?uoroandrostane-3B-ol-17-one. ‘Conversion The novel 16,16-di?uoroandrostanes of the general of, the 3/8-hydroXyl group to the 3-keto is effected by a formula are therapeutically valuable in that they cause , chromic acid oxidation to give 16,16-di?uoroandrostane a reduction in serum cholesterol. This property renders our novel compounds valuable in the treatment and 60 3,17-dione. Alternatively, esteri?cation of ‘the iii-hydrox yl group with p-toluenesulfonic acid in pyridine, for’ eX prevention of diseases which are accompanied by an in crease in serum cholesterol, particularly, for example, in the treatment of atherosclerosis. The preferred species of the therapeutically active 16, by ample, gives 16,16-di?uoroandrostane-3,8-ol-l7-one~3étos-, ylate. Displacement of the 3B-tosylate by sodium acetate ‘ using known techniques to give thecorresponding 3a-ace I toxy-16,l6-di?uoroandrostane-17-one followed by hy 16-di?uoroandrostanes of the general formula as described 65 drolysis with ethanolic potassium hydroxide yields 16,16- ' ‘ herein above is 16,16-di?uoroandrostane-3a-ol-l7-one, di?uoroandrostane-Stat-01717-one of our invention. In like which is useful as an intermediate for preparing the other manner, utilizing similar techniques other 16,16-di?uoro_— 16,16-di?uoro compounds of this invention as well as S-androstenes described in copending application, Serial being therapeutically active per se. No. 7,107, ?led February 8, 1960, such as 16,16-di?uor'o Our novelrcompounds are conveniently prepared from 70 _l7a-methyl-5-androstene-3/8,17,8-diol are convertible to the‘ androsterone (androstane-3a-ol-17-one) by utilizing the novel process ‘described in the copending application of corresponding 16,16-di?uoroandrostanes of this invention, > a in ‘ 3,045,032 4 3 EXAMPLE 3 The 3a-hydroxy-16,16-di?uoroandrostanes of the gen eral formula possessing an ester group at 17, are conven iently prepared by known techniques from the correspond ing 17-hydroxy~l6,16-difluoroandrostane by selective es To a stirred solution of methyl magnesium iodide (pre teri?cation at C-17 with pyridine and a lower alkanoyl lit pared from 3 g. of magnesium and 7.5 ml. of methyl iodide) in 250 ml. of anhydrous ether is added drop anhydride. For example, 16,16-di?uoroandrostane-3a, wise with stirring one gram of 16,16-di?uoroandrostane 17B-diol reacted with approximately a molar equivalent of acetic anhydride in pyridine yields the 17-monoacetate, i.e. 16,l6-di?uoroandrostane-3a,17/3-diol 17-acetate. By substituting other lower alkanoyl anhydrides such as pro pionyl anhydride or caproic anhydride, the corresponding 17-lower alkanoate is obtained, i.e. the 17-propionate and 17-caproate respectively of l6,16-di?uoroandrostane-3u, 17/i-diol. When preparing 3,17-diesters of the general formula, the corresponding 3,17-diol is preferably reacted in pyridine with at least two moles of acid anhydride per mole of steroid. Usually an‘ excess of acid anhydride is used, and it is often desirable to apply heat to hasten the esteri?ca tion process. The following examples are shown by way of illustra tion only and are not to be construed as limiting the scope of our invention, the scope of our invention being 3e-ol-17-one (the compound of Example 1) in 50 ml. of tetrahydrofuran. 150 ml. more of tetrahydrofuran is added and the mixture is distilled until 250 ml. of distillate is collected. The reaction mixture is re?uxed for one hour longer, then cooled and diluted with ice-cold 10% aqueous aluminum sulfate solution. A solid separates which is ?ltered, washed with water, dried and chromatographed on Florisil. Hexane-ether (1:1) eluates are combined and evaporated in vacuo to give 16,16'di?llOr0-17u-I1'16th ylandrostane-3a,17;9-diol. In a similar manner, by substituting other alkyl Grig nard reagents such as ethyl magnesium iodide and n-pro pyl magnesium bromide for methyl magnesium iodide in the above procedure, there is obtained 16,16-di?uoro-17a ethylandrOstane-Ba,17,8-diol and 16,16-di?uoro-17a-n-pro pylaridrostane-3a,17,6-dio1, respectively. de?ned by the appended claims. EXAMPLE 4 EXAMPLE 1 16,16-Di?u0r0androstane-3u,17,8-Di0l 1 6,1 6-Di?uoroandrostane-3 a-Ol-I 7-0ne 500 mg. of 16,16-di?uoroandrostane-3a-ol-17-one (the compound of Example 1) is dissolved in 50 ml. of iso propanol to which is added 900 mg. of sodium borohy A. 16-hydr0xymethyIeneandr0stane-3a-0l-17-0ne.—To a solution of one gram of androsterone in 20 ml. of tetra dride. The solution is heated on the steam bath for one hydrofuran is added one gram of sodium methoxide. While the reaction is stirred under an atmosphere of nitro gen, 8 ml. of ethyl formate is added dropwise over a 30 hour, then cooled and diluted With 150 ml. of water. A minute period. The reaction mixture is then stirred under nitrogen 18 hours at room temperature. Ice and water (150 ml.) is added to give a yellow solution which is stirred and neutralized by the dropwise addition of con cented hydrochloric acid. A solid precipitates which is ?ltered, washed with water’ and dried in vacuo to give 16-di?uoroandrostane-3u,17,8-diol. 1?-hydroxymethyleneandrostane-3a-ol-17-one, AL??? 265 mp (e 9,100) B. 16,16-di?uor0androstane-3a-0l-17-0ne.--To a solu tion of one gram of 16-hydroxymethyleneandrostane-3ot ol-17-one in 150 ml. of t-butanol is added 20 ml. of a one molar solution of potassium in t-butanol. Perchloryl solid precipitates which is ?ltered, washed with water, dried and crystallized from aqueous methanol to give 16. EXAMPLE 5 1 6,1 6 -Di?uoraandrostan 2-3 a,1 7f3-Di0l 1 7-Acetate To 3.28 g. of 16,16-di?uoroandrostane-3a-17?-diol (the 40 compound of Example 4) in 24 ml. of pyridine is added 1.03 ml. of acetic anhydride. The solution is left at room temperature for eight hours, then diluted with water. A solid separates which is ?ltered, washed with Water and dried to give 16,16-di?uoroandrostane-3a,17;3-diol 17-ace tate. By substituting other lower alkanoic acid anhydrides such as propionic or caproic for acetic anhydride in the ?uoride gas is bubbled through the solution at room tem above procedure there is obtained the corresponding 17 perature for 90 minutes. The reaction mixture is then di propionate or 17-caproate respectively of 16,16-di?uoro luted with 500 ml. of water and extracted with methylene androstane-3a,17/3-diol. chloride. The extracts are combined, washed with water and evaporated to a residue which is chromatographed on EXAMPLE 6 Florisil. The hexane-ether (1:1) eluates are combined Alternate Method 0]‘ Preparing 16,16-Di?uor0androstane and evaporated in vacuo to give a residue which is crystal 3124-01-1 7-One lized from hexane-ether to give 16,16-di?uoroandrostane- CA, CI! A. 16-ethoxalylandrostaneda-ol-Z7-one.--To a stirred 3e-ol—l7-one, M.P. l33-l36° G, [0:11) +102". solution of 10 g. of sodium methoxide in 60 ml. of ethyl EXAMPLE 2 oxalate and 60 ml. of benzene under an atmosphere of nitrogen there is ‘added dropwise a solution containing 60 10 g. of androstane-3u-ol~17-one in 5 m1. of benzene and A. 6.5 ml. portion of a 17% suspension of sodium acetylide in xylene is centrifuged and the supernatant liquid removed and replaced by 15 ml. of dimethylsulfox ide. The resultant suspension is added to a stirred solu tion of one gram of 16,16-di?uoroandrostane-3a-ol-17-one in 100 ml. of dirnethylsulfoxide at room temperature. The reaction mixture is stirred at room temperature for 30 minutes, then water and ice are added. A solid separates 100 m1. of tetrahydrofuran. The reaction mixture is stirred under nitrogen at room temperature for 18 hours. The mixture is then ?ltered, poured into 350 ml. of water with stirring and neutralized with 6 N hydrochloric acid. ' A solid separates which is ?ltered, washed with water and dried to give 16-ethoxalylandrostane~3a-ol-17-one which is used without further puri?cation in the following pro cedure. which is ?ltered, washed with water, dried and crystal B. 16,16-di?uoroandrostane-é’u-ol-l7-one.-—16-ethoxal lized from acetone-hexane to give 16,16-di?uoro-17u 70 ylandrostane-3u-ol-17-one is reacted with perchloryl ?uo cthinylandrostane-l3a-17B-diol. ’ ride in t-butanol in the presence of potassium t-butoxide In a similar manner, by substituting sodium methyl in the manner described in Example 113. The resultant acetylidefor sodium acetylide in the above procedure, product is isolated and puri?ed as described to give 16, there is obtained 16,16¢ditluoro-17a-(1-propynyl)-andros tane-3a-l7B-diol. 75 16-di?uoroandrostauc-3a-ol-l7-one. 5 3,045,032 6 EXAMPLE 7 1 6,16-Di?uoroandr0stane-3a-Ol-17-One 3-A cetate To 3.28 g. of 16,16-diiluoroandrostane-3et-ol-17-one We claim: 1. A compound having the following general formula: 0H, (the compound of Example 1) in 24 ml. of pyridine is 5 added 1.03 ml. of acetic anhydride. The solution is 2 CH3 I . F heated on a steam bath for one hour then diluted with water. A solid separates which is ?ltered, washed with water, dried and recrystallized from acetone-hexane to give 16,16-di?uoroandrostane-3a-ol-17-one 3-acetate. F 10 In a similar manner, by substituting other lower alka noic acid 'anhydrides such as propionic or valeric for acetic anhydride in the above procedure there is obtained the corresponding 3-propionate and 3-valerate, respec tively of 16,16-di?uoroandrostane-3 oc-Ol-17-0116. wherein Z is a member of the group consisting of O, 15 H EXAMPLE 8 1 I iloweralkyl OR’ l6,16-Di?uoroandr0stane-3a,17?-Di0l Diacetate lloweralkynyl and I \OR’ wherein R and R’ are members of the group consisting To 3.28 g. of 16,16-Cli?ll01‘03l1dI‘OSt3Il6-3oc,l7l3~di0l (the compound of Example 4) in 50 ml. of pyridine is added 20 of H and an acyl radical of a hydrocarbon carboxylic acid containing up to eight carbon atoms. 2.5 ml. of acetic anhydride. The solution is heated on the steam bath for one hour .then diluted with water. l6-di?uoroandrostane-3a,17,8-diol diacetate. In a similar manner, by substituting other lower alka noic acid anhydrides such as propionic or Valerie for acetic anhydride in the above procedure there is obtained the corresponding 3,17-dipropionate and 3,17-divalerate respectively of 16,16-di?uoroandrostane-3u,17p-diol. gmutson . 16,16-di?uoroandrostane-3u-ol-17-one. A solid separates which is ?ltered, Washed with Water, dried and recrystallized ‘from acetone-hexane to give 16, . 16,16-di?uoroandrostane-3a,17p-diol. . 16,16-di?uoro-l7a-methylandrostane-3u,17/3-di0l. 25 . '16,16-di?uoro-17u-ethinylandrostane-3a,17?-diol. 16,l6-di?noroandrostane-3u-ol-17-one 3-acetate. References Cited in the ?le of this patent Pappo et al.l' “Journal of the American Chemical So ciety,” vol. 78 (1956). Pages 6347-6353 relied on.