United States Patent Office Patented Jan

3,365,473 United States Patent Office Patented Jan. 23, 1968

1. 3,365,473 133-LOWER ALKYL GONA-4,8(14)-DIEN-3-ONES 178 PROCESS FOR THE PRODUCTION THEREOF David Taub, Metuchen, N.J., assignor to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed Dec. 28, 1965, Ser. No. 517,128 15 Claims. (CI. 260-397.3)

ABSTRACT OF THE DISCLOSURE 10. This invention disclosed herein is concerned with a novel synthesis of novel intermediate compounds useful in the synthesis of known steroids of the estrane series which have utility in the pharmaceutical field as gonadotro phin inhibiting agents and which also have progestational 15 activity. More particularly, this invention relates to a synthesis of 13.6-lower alkylgona-4,8(14)-dien-3-one-17B ol or 17-keto steroids (Compound III), 3-hydroxy-136 lower alkylgona-1,3,5 (10),8(14)-tetraen-17 (3-ol, or 17B keto, 17-acetal or ketal steroids (Compound IV). In this 20 synthesis, 3-alkoxy-17B-lower alkyl-gona-1,3,5 (10),8,14 pentaen-17B-ol is reacted with lithium and liquid am monia thereby forming 3 alkoxy-133-lower alkyl gona 2,5 (10),8(14)-triene-176-ol which, upon acidic hydrolysis, is converted to the corresponding 3-keto A-derivative; the latter compound is reacted with N-bromo-succinimide thereby aromatizing ring A to form 8 (14)-dehydro estradiol or other 13-alkyl analog; catalytic hydrogena tion of the last-named compound produces 8-iso estradiol 30 The starting material, Compound II, may be prepared or other 13-alkyl analog which is reacted with an etherify by the reduction of a 3-hydroxy or substituted oxy-1718 ing agent to from the corresponding 3-alkyl ether; sodium lower alkyl-1,3,5 (10),8,14-pentaen-17f8-ol, 17-keto, or 17 dichromate oxidation of the latter forms 8-isoestrone 3 acetal or ketal (Compound I) with an alkali metal, pref alkyl ether which is reacted with chloranil to form the erably lithium, in liquid ammonia. The reduction is ac corresponding 3-alkyl ether of 8-dehydroestrone; this com complished by adding a solution of Compound I in a pound is then reacted with sodium in liquid ammonia suitable solvent, such as a mixture of tetrahydrofuran and thereby reducing the A8-bond to form the 3-alkyl ether ether, to liquid ammonia, which is maintained at a tem of estradiol which upon oxidation with chromic acid solu perature of from about -50 to -60° C. Anhydrous tion is converted estrone 3-alkyl ether. lower aliphatic alcohol is added with vigorous stirring to 40 a solution in liquid ammonia and after the addition is complete, alkali metal is gradually added in small por This novel synthesis of this invention, in which the tions. The reaction mixture is allowed to stand for a few starting material is a 3-hydroxy or substituted oxy-136 minutes and then an additional amount of lower aliphatic lower alkylgona-2,5(10),8(14)-trien-17B-ol, 17-keto, or alcohol is added. The temperature of the reaction mixture 17-acetal or ketal (Compound II), may be schematically is allowed to come slowly to room temperature and the represented as follows, wherein R1 is hydrogen, a lower ammonia is allowed to evaporate. Water is added to the alkyl or cycloaliphatic substituent, preferably having not residue and most of the lower aliphatic alcohol is re more than five carbon atoms, or a heterocylic Substituent, moved from the reaction mixture of distillation under such as a tetrahydropyranyl group; R2 is a g-hydroxy, reduced pressure. The concentrate is extracted with a keto, acetal or ketal group, preferably a 17, 17-ethylene 50 suitable solvent, such as chloroform, the extract is washed dioxy group, R is a lower alkyl group, preferably having with saturated aqueous sodium chloride solution, dried not more than five carbon atoms; RA is a B-hydroxy, over magnesium sulfate, filtered, and concentrated to dry acetal, or ketal group; and R5 is a g-hydroxy or keto ness under reduced pressure. The residue of Compound II group: may be recrystallized from a suitable solvent, such as 55 methanol or a methanol water solution. The 17f8-hydroxy group of Compound II may be oxi l, dized to a keto group by oxidation with chromium trioxide in pyridine solution. The chromium trioxide in pyridine

- solution is added to a pyridine solution of the compound 60 to be oxidized. Oxidation may also be accomplished by adding a solution of the compound to be oxidized in a ot solvent, such as dry benzene or toluene, containing fresh I ly distilled aluminum is propoxide, allowing the solution to stand under nitrogen for a few minutes and then adding 65 cyclohexanone, followed by heating the reaction mix ture on a steam bath. 3,365,473 3 4 The first step in the synthesis is the treatment of a solu (Compound VII). Oxidation of the 178-hydroxy group tion of Compound II in an organic solvent, preferably of Compound VI may be accomplished by conventional acetic acid, with a strong acid, such as hydrochloric, methods, such as by oxidation with sodium dichromate in sulfuric, or phosporic acid, at an elevated temperature to acetic acid solution. Oxidation may also be accomplished provide Compound III. Treatment of Compound II with by adding a solution of the compound to be oxidized in a strong acid at an elevated temperature, preferably 70' a solvent, such as dry benzene or toluene, containing to 90° C., converts a 17-acetal or ketal group to a 17-keto freshly distilled aluminum isopropoxide, allowing the group and simultaneously converts the enol or enol ether solution to stand under nitrogen for a few minutes and linkage on the A-ring to a 3-keto group. The first step in then adding cyclohexanone, followed by heating the reac the synthesis may be accomplished by heating a solution O tion mixture on a steam bath. of Compound i in acetic acid containing a strong mineral Compound VII is oxidized to provide a 3-methyl ether acid, preferably hydrochloric acid, at a temperature of of 3-hydroxy-13-lower alkylgona-1,3,5(10), 8-tetraen about 90° C. for a few minutes, the reaction mixture 17-one steroid (Compound VIII). Oxidation is ac being kept under nitrogen during the heating period. After complished by refluxing under nitrogen a solution of Com the heating period, the mixture is cooled, poured into ice 5 pound VII in a lower aliphatic alcohol, preferably water, and the resulting mixture is extracted with a suit tertiary-butanol, containing chloranil. The reaction prod able solvent, such as ether or chloroform. The extract is uct is isolated by filtering the reaction mixture, removing washed with 5% aqueous potassium bicarbonate solution, the solvent by distillation under reduced pressure and and then washed with saturated aqueous sodium chloride dissolving the residue in chloroform. The chloroform solution. The washed extract is dried over magnesium sul 20 solution is allowed to stand overnight and then filtered to fate, filtered, and concentrated to dryness under reduced remove tetrachlorohydroquinone. This solution is washed pressure. The residue may be crystallized from a suitable repeatedly with water, dried over anhydrous sodium sul solvent, such as methanol. fate, filtered, and evaporated to dryness under reduced The second step in the synthesis is the aromatization pressure. The residue is dissolved in methanol and treated of the A-ring of Compound III to provide Compound IV 25 with charcoal. The charcoal is removed by filtration and The aromatization of the A-ring of Compound III may the oxidized product, Compound VIII is crystallized from be accomplished by refluxing a mixture of Compound a suitable solvent, such as methanol or ethyl acetate. III and N-bromosuccinimide in a suitable organic sol Compound VIII may be converted to the 3-methyl vent such as carbon tetrachloride, under nitrogen. During ether of a 3-hydroxy 13-lower alkylgona-1,3,5 (10)-trien part of the reflux period, the reaction mixture is il 30 176-ol steroid by reduction of the A8-bond of Compound luminated with a photo flood lamp. After refluxing, the VIII with sodium or potassium in liquid ammonia. If a reaction mixture is cooled, washed with 5% aqueous keto group is present on the 17-carbon atom of Com potassium bicarbonate solution, dried over magnesium pound VIII, reduction with sodium or potassium in liquid sulfate, filtered, and concentrated to dryness under re ammonia also results in reduction of the 17-keto group duced pressure. The residue may be purified by 35 to a 17,3-hydroxy group. The 17g-hydroxy group may be chromatography on silica gel, using benzene as a solvent oxidized to a 17-keto group by conventional methods, and recovering the chromatographed product by elution such as oxidation with concentrated aqueous chromic acid with a solvent composed of 90% chloroform and 10% solution or oxidation with aluminum isopropoxide in the methanol. The product may be further purified by crystal presence of cyclohexanone to provide a 3-methyl ether of lization from a suitable solvent, such as methanol. 40 a 3-hydroxy - 13-lower alkylgona-1,3,5(10)-trien-17-one Compound IV may be used in a synthesis of 13.6-lower steriod. alkylgona-1,3,5 (10)-trien-17-one-3-ol steroids, such as A 3-hydroxy-13-lower alkylgona-1,3,5(10)-trien-17-one estrone and lower alkyl ethers thereof. The first step in steroid may also be obtained by shifting the A8-bond this synthesis is catalytic hydrogenation of Compound IV of Compound VIII to the A9(11)-position to provide a to provide a 3-hydroxy-136-lower alkyl-8-isogona-1,3,5- 45 3-methyl ether of a 3-hydroxy-13-lower alkylgona-1,3, (10)-trien-178-ol or 17-keto steroid (Compound IV). 5 (10),9(11)-tetraen-17-one steroid and hydrogenating Hydrogenation of Compound IV is conveniently ac the latter compound. The A8-bond of Compound VIII complished by shaking a 95% ethanol solution of Com is shifted to the A9(11)-position by refluxing Com pound IV containing 10% palladized charcoal under one pound VIII with methanolic hydrochloric acid. The atmosphere of hydrogen and at room temperature until 50 3-methyl ether of a 3-hydroxy-13-lower alkylgona-1,3, an equimolar amount of hydrogen is absorbed. Compound 5 (10),9(11)-tetraen-17-one steroid precipitate out upon V may be isolated from the reaction mixture by removing cooling the reaction mixture and may be recrystallized the catalyst by filtration and removing the Solvent by from a methanol-ethanol solution. The latter compound distillation under reduced pressure. The residue is Com may be catalytically hydrogenated by shaking a solution pound V and may be purified by crystallization from a 55 thereof in ethanol containing 10% palladized charcoal suitable solvent, such as methanol. with hydrogen until one molecular equivalent of hydro In the next step, the 3-hydroxy group of Compound V gen has been absorbed, filtering, removing the solution is etherified. Etherification of Compound V, which has by distillation under reduced pressure and crystallizing a 179-hydroxy or a 17-keto group to provide the methyl the residue from a suitable solvent, such as methanol. ether of a 3-hydroxy-136-lower alkyl-8-isogona-1,3,5 (10)- 60 The hydrogenation product is a 3-hydroxy-13-lower alkyl trien-176-ol or 17-one steroid, (Compound VI), may be gona-1,3,5(10)-trien-17-one steroid. conveniently accomplished by refluxing an ethanol solu The following preparations illustrate methods of pre tion of Compound V containing dimethylsulfate and a paring the starting material, Compound II. strong inorganic base, such as potassium hydroxide or PREPARATION 1 sodium hydroxide. The methyl ether may be conveniently 65 isolated by pouring the reaction mixture into Water, ex 3-methoxy-17,17-ethylenedioxyestra tracting with ether, washing the ether extract with dilute aqueous potassium hydroxide solution, then Washing with 2,5 (10),8(14)-triene water, drying the ether extract over magnesium sulfate, A solution of 1 g of 3-methoxy-17, 17-ethylenedioxy filtering and removing the solvent by distillation under estra-1,3,5(10),8,14-pentaene in 25 ml. of tetrahydro reduced pressure. The residue of Compound VI may be 70 furan and 30 ml. of ether is added to 150 ml. of anhy crystallized from a suitable solvent, such as methanol. drous liquid ammonia while the temperature of the am If Compound VI has a 17B-hydroxy group, it may be monia is within the range of -50 to - 60° C. Eighty oxidized to provide a 3-methyl ether of 3-hydroxy-13 milliiiters of anhydrous ethanol is added with vigorous lower alkyl-8-isogona - 1,3,5 (10)-trien-17-one steroid 5 stirring and then 4 g. of lithium are added in small pieces 8,365,473 5 6 over a 10-minute period. The reaction mixture is allowed minute period. The reaction mixture is allowed to stand to stand for 15 minutes and then 10 mil. of ethanol are for 15 minutes and then 10 ml. of ethanol are added. The added. The reaction mixture is allowed to come slowly to reaction mixture is allowed to come slowly to room tem room temperature so that the ammonia evaporates over perature so that the ammonia evaporates overnight. One night. One hundred milliliters of water are added to the hundred milliliters of water are added to the residue and residue and the mixture is concentrated to dryness under the mixture is concentrated to dryness under reduced reduced pressure to remove most of the ethanol. The pressure to remove most of the ethanol. The residual mix residual mixture is extracted with chloroform, the extract ture is extracted with chloroform, the extract is washed is washed with saturated aqueous sodium chloride solu with saturated aqueous sodium chloride solution, dried tion, dried over magnesium sulfate, filtered, and concen 0 over magnesium sulfate, filtered, and concentrated to dry trated to dryness under reduced pressure. One gram of ness under reduced pressure. One gram of crude 3-ethoxy crude 3 - methoxy - 17, 17 - ethylenedioxyestra-2,5(10),8 136-n-butylgona-2,5(10),8(14)-trien-176-ol is obtained. (14)-triene is obtained. The crude product is purified by The crude product is purified by crystallization from crystallization from methanol. methanol. 5 The following examples illustrate methods of carrying PREPARATION 2 out the present invention, but it is to be understood that 3-methoxy-13,3-ethylgona-2,5(10),8(14)-trien-176-ol these examples are given for purposes of illustration and A solution of 1. g. of 3-methoxy-136-ethylgona-1,3,5- not of limitation. (10),8,14-pentaen-17B-ol in 25 ml. of tetrahydrofuran EXAMPLE 1. and 30 ml. of ether is added to 150 ml. of anhydrous 20 13.6-methylgona-4,8(14)-diene-3,17-dione liquid ammonia while the temperature of the ammonia is A solution of 1 g. of 13.6-methyl-17, 17-ethylene-dioxy within the range of -50 to -60° C. Eighty milliliters gona-2,5(10),8(14)-trien-3-ol methyl ether in 10 ml. of of anhydrous ethanol is added with vigorous stirring and acetic acid and 5 ml. of N-hydrochloric acid is kept then 4 g. of lithium are added in small pieces over a 10 25 under nitrogen at 90° C. for 10 minutes. The mixture is minute period. The reaction mixture is allowed to stand cooled, poured into 100 ml. of iced water, and extracted for 15 minutes and then 10 ml. of ethanol are added. The with chloroform. The extract is separated and washed reaction mixture is allowed to come slowly to room tem with 5% aqueous potassium bicarbonate solution, washed perature so that the ammonia evaporates overnight. One with saturated aqueous sodium chloride solution, dried hundred milliliters of water are added to the residue and 30 over magnesium sulfate, filtered, and concentrated to dry the mixture is concentrated to dryness under reduced pres ness under reduced pressure. The residue of 13.6-methyl sure to remove most of the ethanol. The residual mixture gona-4,8(14)-diene-3,17-dione is crystallized from metha is extracted with chloroform, the extract washed with nol and the recrystallized product has a melting point of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness 155-158 C. Ama. 234 mu (Em 15,510). under reduced pressure. One gram of crude 3-methoxy EXAMPLE 2 136-ethylgona-2,5(10),8(14)-trien-176-ol is obtained. The A8(14)-dehydroestrone crude product is purified by crystallization from methanol. A mixture of 270 mg. of 13.6-methylgona-4,8(14)-diene PREPARATION 3 3,17-dione and 200 mg. of N-bromosuccinimide in 30 ml. 40 of carbon tetrachloride is refluxed under nitrogen and 3-tetrahydropyranyloxy-133-isopropylgona illumination with a photo flood lamp for 2 minutes and 2,5 (10),8(14)-trien-173-ol then refluxed for 5 minutes without illumination. The re A solution of 1 g. of 3-tetrahydropyranyloxy-13,3-iso action mixture is cooled, washed with 5% aqueous potas propylgona-1,3,5 (10),8,14-pentaen-176-ol in 25 ml. of sium bicarbonate solution, dried over magnesium sulfate, tetrahydrofuran and 30 ml. of ether is added to 150 ml. 45 filtered and concentrated to dryness under reduced pres of anhydrous liquid ammonia while the temperature of sure. The residue of A8(4)-dehydroestrone is purified by the ammonia is within the range of -50 to -60° C. chromatography on silica gel, using benzene as a develop Eighty milliliters of anhydrous ethanol is added with ing solvent and using a solvent composed of 90% chloro vigorous stirring and then 4.g. of lithium are added in 50 form and 10% methanol to elute the A8(14)-dehydroes small pieces over a 10-minute period. The reaction mix trone from the chromatogram. ture is allowed to stand for 15 minutes and then 10 ml. EXAMPLE 3 of ethanol are added. The reaction mixture is allowed to come slowly to room temperature so that the ammonia 8-isoestrone evaporates overnight. One hundred milliliters of water 55 0.134 grams of 8(14)-dehydroestrone in solution in 30 are added to the residue and the mixture is concentrated ml. of 95% ethanol containing 0.1 g of 10% palladium to dryness under reduced pressure to remove most of the on charcoal is hydrogenated at room temperature and ethanol. The residual mixture is extracted with chloro atmospheric pressure until one molecular equivalent of form, the extract is washed with saturated aqueous sodium hydrogen is absorbed. The catalyst is removed by filtration chloride solution, dried over magnesium sulfate, filtered, 60 and the ethanol is removed by distillation under reduced and concentrated to dryness under reduced pressure. One pressure. The residue is 8-isoestrone and is purified by re gram of crude 3-tetrahydropyranyloxy - 136 - isopropyl crystallization from methanol. The recrystallized material gona-2,5(10),8(14)-trien-17B-ol is obtained. The crude has a melting point of 252-254 C. U.V. spectrum (meth product is purified by crystallization from methanol. anol): Nmax. 281 (E 2,160). 65 PREPARATION 4 EXAMPLE 4 3-ethoxy-13,3-n-butylgona-2,5(10),8(14)-trien-176-ol 8-isoestrone methyl ether Three milliliters of dimethylsulfate are added dropwise A solution of 1 g. of 3-ethoxy-136-n-butylgona to a solution of 0.192 g. of 8-isoestrone in 30 ml. of etha 1,3,5(10),8,14-pentaen-176-ol is 25 ml. of tetrahydrofuran 70 nol containing 5 g. of potassium hydroxide and the mix and 30 ml. of ether is added to 150 ml. of anhydrous liq ture is refluxed for four hours under nitrogen. The solu uid ammonia while the temperature of the ammonia is tion is poured into 150 ml. of water and the aqueous solu within the range of -50 to -60° C. Eighty milliliters tion is extracted with ether. The ether solution is washed of anhydrous ethanol is added with vigorous stirring and with 5% aqueous potassium hydroxide solution then with then 4 g. of lithium are added in small pieces over a 10 75 water until neutral. The ether solution is dried over mag 3,365,473 7 8 nesium sulfate and the ether is removed by distillation EXAMPLE 9 under reduced pressure. The residue of 8-isoestrone meth 136-ethyl-8-isogona-1,3,5 (10)-triene-3,176-diol yl ether is recrystallized twice from methanol and has a methyl ether M.P. of 152.5-153.5° C. Three milliliters of dimethylsulfate are added dropwise Analysis.-Calcd. for C18H4O (284.32): C, 80.24; H, ) to a solution of 0.192 g. of 13 (3-ethyl-8-isogona-1,3,5 (10)- 8.51. Found: C, 80.25; H, 8.64. triene-3,176-diol in 30 ml. of ethanol containing 5 g. of potassium hydroxide and the mixture is refluxed for four EXAMPLE 5 hours under nitrogen. The solution is poured into 150 ml. 8-dehydroestrone methyl ether of water and the aqueous solution is extracted with ether. O The ether solution is washed with 5% aqueous potassium A solution of 0.12 g. of 8-isoestrone methyl ether in hydroxide solution then with water until neutral. The solution in 12 ml. of tertiary-butanol containing 0.12 g. ether solution is dried over magnesium sulfate and the of chloranil is refluxed for six hours under nitrogen. The ether is removed by distillation under reduced pressure. reaction mixture is filtered and the tertiary-butanol is re The residue of 136 - ethyl-8-isogona-1,3,5 (10)-triene moved by distillation under reduced pressure. The residue 3,176-diol methyl ether is recrystallized twice from is dissolved in chloroform and the chloroform solution is methanol. allowed to stand overnight and then filtered to remove the EXAMPLE 10 tetrachlorohydroquinone. The filtrate is washed repeated ly with water and the chloroform solution is dried over 13,3-ethyl-8-isogona-1,3,5 (10)-trien-3-ol-17-one anhydrous sodium sulfate. The chloroform solution is 20 methyl ether concentrated to dryness by distillation under reduced pres A solution of 282 mg. of 138-ethyl-8-isogona-1,3,5(10)- sure. The residue is dissolved in methanol and treated with triene-3,17-diol methyl ether and 99 mg. of sodium di charcoal. The charcoal is removed by filtration and the 8 chromate and 10 ml. of glacial acetic acid is kept at 25 dehydroestrone methyl ether is crystallized from the con C. for six hours. Water is added and the reaction mix centrated methanol solution and then from ethyl acetate. ture is extracted with chloroform. The chloroform extract The recrystallized product has a M.P. of 121-123° C. is washed with 5% aqueous potassium bicarbonate solu U.V. spectrum (dioxane): Ama. 280 (E 16,000). tion, washed with saturated aqueous sodium chloride solu tion, dried over magnesium sulfate, filtered and concen EXAMPLE 6 trated to dryness under reduced pressure. The residue is 13.6-ethyl-8-isogona-1,3,5 (10)-trien-3-ol - 17 - one methyl 136-ethylgona-4,8(14)-dien-17B-ol-3-one ether and is obtained in crystalline form by trituration A solution of 1 g, of 3-methoxy-13 (3-ethylgona-2,5(10), with methanol. The product may be recrystallized from 8(14)-trien-17B-ol in 10 ml. of acetic acid and 5 ml. of methanol. 1 N-hydrochloric acid is kept under nitrogen at 90° C. EXAMPLE 11 for 10 minutes. The mixture is cooled, poured into 100 13{3-ethylgona-1,3,5 (10),8-tetraen-3-ol-17-one ml. of iced water, and extracted with chloroform. The methyl ether extract is separated and washed with 5% aqueous po A solution of 0.12 g. of 136-ethyl-8-isogona-1,3,5(10)- tassium bicarbonate solution, washed with saturated aque trien-3-ol-17-one methyl ether in solution in 12 ml. of ous sodium chloride solution, dried over magnesium sul 40 tertiary-butanol containing 0.12 g. of chloranil is refluxed fate, filtered, and concentrated to dryness under reduced for six hours under nitrogen. The reaction mixture is pressure. The residue of 136-ethylgona-4,8(14)-dien-17 (3- filtered and the tertiary butanol is removed by distillation ol-3-one is crystallized from methanol. under reduced pressure. The residue is dissolved in chloro form and the chloroform solution is allowed to stand EXAMPLE 7 overnight and then filtered to remove the tetrachloro 138-ethylgona-1,3,5 (10),8(14)-tetraene-3,176-diol hydroquinone. The filtrate is washed repeatedly with water and the chloroform solution is dried over anhy A mixture of 270 mg. of 13.6-ethylgona-4,8(14)-dien drous sodium sulfate. The chloroform solution is concen 176-ol-3-one and 200 mg. of N-bromosuccinimide in 30 rated to dryness by distillation under reduced pressure. ml. of carbon tetrachloride is refluxed under nitrogen and 50 The residue is dissolved in methanol and treated with illumination with a photo flood lamp for 2 minutes and charcoal. The charcoal is removed by filtration and the then refluxed for 5 minutes without illumination. The re 136-ethylgona-1,3,5(10),8-tetraen-3-ol - 17 - one methyl action mixture is cooled, washed with 5% aqueous po ether is crystallized from the concentrated methanol solu tassium bicarbonate solution, dried over magnesium sul tion and then from ethyl acetate. fate, filtered and concentrated to dryness under reduced 55 pressure. The residue of 136-ethylgona-1,3,5 (10),8(14)- EXAMPLE 12 tetraene-3,175-diol is purified by chromatography on 13-6-isopropylgona-4,8(14)-diene-176-hydroxy-3-one silica gel, using benzene as a developing solvent on a sol A solution of 1 g. of 3-tetrahydropyranyloxy-13 6-iso vent composed of 90% chloroform and 10% methanol propylgona-2,5(10),8(14)-trien-176-ol in 10 ml. of acetic to elute the 136-ethylgona-1,3,5 (10),8(14)-tetraene-3,178, 60 acid and 5 ml. of 1 N-hydrochloric acid is kept under diol from the chromatogram. nitrogen at 90° C. for 10 minutes. The mixture is cooled, poured into 100 ml. of iced water, and extracted with EXAMPLE 8 chloroform. The extract is separated and washed with 13,3-ethyl-8-isogona-1,3,5 (10)-triene-3,1713-diol 5% aqueous potassium bicarbonate solution, washed with Saturated aqueous Sodium chloride solution, dried over 0.134 grams of 13,3-ethylgona-1,3,5 (10),8, (14)-tetra magnesium Sulfate, filtered, and concentrated to dryness ene-3,179-diol in solution in 30 ml. of 95% ethanol con under reduced pressure. The residue of 136-isopropylgona taining 0.1 g of 10% paladium on charcoal is hydro 4,8(14)-diene-17g-hydroxy-3 - one is crystallized from genated at room temperature and atmospheric pressure methanol. until one molecular equivalent of hydrogen is absorbed. EXAMPLE 13 The catalyst is removed by filtration and the ethanol is removed by distillation under reduced pressure. The resi 13g-isopropylgona-1,3,5(10),8(14)-tetraene-3,176-diol due is 136-ethyl-8-isogona-1,3,5 (10)-triene-3,176-diol, and A mixture of 270 mg. of 133-isopropylgona-4,8(14)- is purified by recrystallization from ethanol. 75 diene-176-hydroxy-3-one and 200 mg. of N-bromosuc 3,365,478 9 10 cinimide in 30 ml. of carbon tetrachloride is refluxed un anhydrous sodium sulfate. The chloroform solution is der nitrogen and illumination with a photo flood lamp for concentrated to dryness by distillation under reduced 2 minutes and then refluxed for 5 minutes without ill pressure. The residue is dissolved in methanol and treated lumination. The reaction mixture is cooled, washed with 5% aqueous potassium bicarbonate solution, dried over with charcoal. The charcoal is removed by filtration and magnesium sulfate, filtered and concentrated to dryness the 3-methoxy-136-isopropylgona-1,3,5(10),8-tetraen-17 under reduced pressure. The residue of 136- isopropyl one is crystallized from the concentrated methanol solu gona-1,3,5(10),8(14)-tetraene-3,176-diol is purified by tion and then from ethyl acetate. chromatography on silica gel, using benzene as a develop EXAMPLE 18 ing solvent on a solvent composed of 90% chloroform 0. 136-n-butylgona-4,8(14)-diene-176-hydroxy-3-one and 10% methanol to elute the 133-isopropylgona-1,3, A solution of 1 g. of 3-ethoxy-13g-n-butylgona-2,5- 5 (10),8(14)-tetraene-3,176-diol from the chromatogram. (10),8(14)-trien-17B-ol in 10 ml. of acetic acid and 5 EXAMPLE 1.4 ml. of 1 N-hydrochloric acid is kept under nitrogen at 90° C. for 10 minutes. The mixture is cooled, poured into 133-isopropyl-8-isogona-1,3,5(10)-triene-3,176-diol 100 ml. of iced water, and extracted with chloroform. The extract is separated and washed with 5% aqueous 0.134 grams of 133-isopropylgona-1,3,5(10),8(14)- potassium bicarbonate solution, washed with saturated tetraene-3,176-diol in solution in 30 ml. of 95% ethanol aqueous sodium chloride solution, dried over magnesium containing 0.1 g. of 10% palladium on charcoal is hy sulfate, filtered, and concentrated to dryness under re drogenated at room temperature and atmospheric pres 20 sure until one molecular equivalent of hydrogen is ab duced pressure. The residue of 136-n-butylgona-4,8(14)- sorbed. The catalyst is removed by filtration and the diene-17 (3-hydroxy-3-one is crystallized from methanol. ethanol is removed by distillation under reduced pres EXAMPLE 19 sure. The residue is 136-isopropyl-8-isogona-1,3,5(10)- triene-3,176-diol and is purified by recrystallization from 25 136-n-butylgona-1,3,5 (10),8(14)-tetraene-3,176-diol methanol. A mixture of 270 mg. of 136-n-butylgona-4,8(14)- EXAMPLE 1.5 diene-176-hydroxy-3-one and 200 mg. of N-bromosuccin imide in 30 ml. of carbon tetrachloride is refluxed under 3-methoxy-138-isopropylgona-8-isogona-1,3,5 (10)- nitrogen and illumination with a photo flood lamp for 2 trien-176-ol 30 minutes and then refluxed for 5 minutes without illu mination. The reaction mixture is cooled, washed with Three milliliters of dimethylsulfate are added dropwise 5% aqueous potassium bicarbonate solution, dried over to a solution of 0.192 g. of 133-isopropyl-8-isogona-1,3,- magnesium sulfate, filtered and concentrated to dryness 5 (10)-triene-3,17(3-diol in 30 ml. of ethanol containing under reduced pressure. The residue of 136-n-butylgona 5 g. of potassium hydroxide and the mixture is refluxed 1,3,5(10),8(14)-tetraene-3,176-diol is purified by chro for four hours under nitrogen. The solution is poured into 35 matography on silica gel, using benzene as a delevolping 150 ml. of water and the aqueous solution is extracted with ether. The ether solution is washed with 5% aqueous solvent on a solvent composed of 90% chloroform and potassium hydroxide solution then with water until neu 10% methanol to elute the 13(3-n-butylgona-1,3,5(10),8- tral. The ether solution is dried over magnesium sulfate (14)-tetraene-3,176-diol from the chromatogram. and the ether is removed by distillation under reduced 40 EXAMPLE 2.0 pressure. The residue of 3-methoxy-136-isopropyl-8-iso gona-1,3,5(10)-trien-175-ol is recrystallized twice from 136-n-butyl-8-isogona-1,3,5 (10)-triene-3,176-diol methanol. 0.134 grams of 13{3-n-butylgona-1,3,5 (10),8(14)-tet raene-3,176-diol in solution in 30 ml. of 95% ethanol EXAMPLE 16 45 containing 0.1 g of 10% palladium on charcoal is hydro 3-methoxy-136-isopropyl-8-isogona-1,3,5 (10)- genated at room temperature and atmospheric pressure trien-17-one until one molecular equivalent of hydrogen is absorbed. The catalyst is removed by filtration and the ethanol is A solution of 282 mg. of 3-methoxy-133-isopropyl-8- removed by distillation under reduced pressure. The isogona-1,3,5 (10)-trien-17 3-ol and 99 mg. of sodium di 50 residue is 136-n-butyl-8-isogona-1,3,5 (10)-triene-3,178 chromate and 10 ml. of glacial acetic acid is kept at diol and is purified by recrystallization from ethanol. 25° C. for six hours. Water is added and the reaction mixture is extracted with chloroform. The chloroform EXAMPLE 21. extract is washed with 5% aqueous potassium bicarbonate 3-methoxy-136-n-butyl-8-isogona-1,3,5(10)-trien-178-ol solution, washed with saturated aqueous sodium chloride 55 solution, dried over magnesium sulfate, filtered and con Three mililiters of dimethylsulfate are added dropwise centrated to dryness under reduced pressure. The residue to a solution of 0.192 g. of 136-n-butyl-8-isogona-1,3,5- is 3-methoxy-136-isopropyl-8-isogona-1,3,5(10)-trien-17 (10)-triene-3,176-diol in 30 ml. of ethanol containing 5 g. one and is obtained in crystalline form by trituration with of potassium hydroxide and the mixture is refluxed for methanol. The product may be recrystallized from 60 four hours under nitrogen. The solution is poured into 150 methanol. ml. of water and the aqueous solution is extracted with ether. The ether solution is washed with 5% aqueous po EXAMPLE 1.7 tassium hydroxide solution then with water until neutral. 3-methoxy-13,3-isopropylgona-1,3,5 (10),8-tetraen-17-one The ether solution is dried over magnesium sulfate and the ether is removed by distillation under reduced pressure. A solution of 0.12 g. of 3-methoxy-136-isopropyl-8- 65 The residue of 3-methoxy-138-n-butyl-8-isogona-1,3,5 isogona-1,3,5(10)-trien-17-one in solution in 12 ml. of (10)-trien-17,3-ol is recrystallized twice from methanol. tertiary-butanol containing 0.12 g. of chloranil is refluxed for six hours under nitrogen. The reaction mixture is .EXAMPLE 22 filtered and the tertiary-butanol is removed by distilla 70 3-methoxy-136-n-butyl-8-isogonal-1,3,5(10)-trien-17-one tion under reduced pressure. The residue is dissolved in A Solution of 282 mg. of 3-methoxy-138-n-butyl-8-iso chloroform and the chloroform solution is allowed to gona-1,3,5 (10)-trien-17(3-ol and 99 mg. of sodium di stand overnight and then filtered to remove the tetra chromate and 10 ml. of glacial acetic acid is kept at 25° C. chlorohydroquinone. The filtrate is washed repeatedly for six hours. Water is added and the reaction mixture is with water and the chloroform solution is dried over 75 extracted with chloroform. The chloroform extract is 3,365,473 12 washed with 5% aqueous potassium bicarbonate solution, 5. A process for the preparation of a compound of the washed with saturated aqueous sodium chloride solution, formula: dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is 3-methoxy 136-n-butyl-8-isogona-1,3,5(10)-trien-17-one and is ob tained in crystalline form by trituration with methanol. The product may be recrystallized from methanol. EXAMPLE 23 N/NZ 3-methoxy-136-n-butylgona-1,3,5 (I0),8-tetraen-17-one 0. A solution of 0.12 g. of 3-methoxy-13,3-n-butyl-8-iso al) gona-1,3,5(10)-trien-17-one in solution in 12 ml. of ter wherein R3 is a lower alkyl radical and R5 is a g-hydroxy tiary-butanol containing 0.12 g. of chloroanil is refluxed or keto group, which comprises refluxing a solution in a for six hours under nitrogen. The reaction mixture is halogenated organic solvent containing N-bromoSuccini filtered and the tertiary-butanol is removed by distilla 5 mide of a compound of the formula: tion under reduced pressure. The residue is dissolved in chloroform and the chloroform solution is allowed to stand overnight and then filtered to remove the tetra chlorohydroquinone. The filtrate is washed repeatedly with water and the chloroform solution is dried over anhy 20 drous sodium sulfate. The chloroform solution is concen trated to dryness by distillation under reduced pressure. The residue is dissolved in methanol and treated with charcoal. The charcoal is removed by filtration and the 3-methoxy-138-n-butylgona-1,3,5 (10),8-tetraen-17-one is 25 crystallized from the concentrated methanol solution and wherein R3 and Rs have the same significance as above. then from ethyl acetate. 6. A process according to claim 5 in which R3 is methyl Various changes and modifications may be made in and R5 is a keto group. carrying out the present invention without departing from 7. A process according to claim 5 in which R3 is methyl, the spirit and scope thereof. Insofar as these changes and 30 R5 is a keto group and the halogenated organic solvent is modifications are within the purview of the annexed carbon tetrachloride. claims, they are to be considered as part of our invention. 8. A process for the preparation of a compound of the What is claimed is: formula: 1. A process for the preparation of a compound of the R5 formula: R3

Né 40 H IO wherein R3 is allower alkyl radical and R5 is a 3-hydroxy or a keto group, which comprises a first step of heating 45 with a strong mineral acid at an elevated temperature of wherein R is a lower alkyl radical, and R5 is a 3-hydroxy approximately 70 to 90° C. a solution in an organic acid or keto group, which comprises heating with a strong Solvent of a compound of the formula: mineral acid at an elevated temperature of approximately 70 to 90° C. a solution in an organic acid solvent of a compound of the formula: Ri () 55 /Né wherein R1 is hydrogen, a lower alkyl, cycloaliphatic, or ir tetrahydropyranyl substituent, R8 has the same significance 60 as above, and R4 is a 6-hydroxy-keto, acetal, or ketal group, to provide a compound of the formula: wherein R is hydrogen, a lower alkyl, cycloaliphatic, or tetrahydropyranyl substituent, R3 has the same significance as above, and R4 is a 6-hydroxy, keto, acetal, or ketal group. 2. A process according to claim 1 in which the organic acid solvent is acetic acid and the strong mineral acid is hydrochloric acid. 3. A process according to claim 1 in which R1 is methyl, R is methyl, R is a 17,17-ethylenedioxy group, and R5 is 70 a keto group. 4. A process according to claim 1 in which R1 is methyl, wherein R3 and Rs have the same significance as above, R is methyl, R is a 17, 17-ethylenedioxy group, R5 is a and a second step of refluxing a solution of the latter keto group, and in which the organic acid solvent is acetic compound in a halogenated organic solvent containing N acid and the strong mineral acid is hydrochloric acid. 75 bromosuccinimide. 3,365,473 13 4 9. A process according to claim 8 in which R1 is methyl, wherein R3 is a lower alkyl radical and R5 is a 3-hydroxy R4 is a 17, 17-ethylenedioxy group, and R5 is a keto group. or keto group. 10. A process according to claim 8 in which, in the first step, the organic acid solvent is acetic acid and the 12. A compound according to claim 1 in which R3 is strong acid is hydrochloric acid, and in the second step, methyl and R5 is a keto group. the halogenated organic solvent is carbon tetrachloride. 13. A compound according to claim 11 in which R3 is 11. A compound of the formula: methyl and R5 is a 3-hydroxy group.

14. A compound according to claim 11 in which R is ethyl and R5 is a keto group. 15. A compound according to claim 11 in which R is 10 ethyl and R5 is a B-hydroxy group. No references cited. ELBERT L. ROBERTS, Primary Examiner.