United States Patent Office Patented Jan
Total Page：16
File Type：pdf, Size：1020Kb
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).