Patented Oct. 20, 1953 2,656,364 UNITED STATES PATENT OFFICE 2,656,364 PROCESS FOR THE MANUFACTURE OF 1-KETO STERO OS Emanuel B. Hershberg, West Orange, N. J., and Eugene P. Oliveto, Long Island City, N. Y., as signors to Schering Corporation, Bloomfield, N. J., a corporation of New Jersey No Drawing. Application July 16, 1951, Serial No. 237,079 23 Claims. (C. 260-397.3) 1. 2 The present invention relates to the manufac We have found that when this last-mentioned ture of 17-ketosteroids, and more particularly to reaction is applied to A16-steroids having an ali the degradation of 20-keto steroids to 17-keto phatic group of one or more carbon atoms at the Steroids. 17-position, and containing ketonic OXygen. On It is the general object of the present inven 5 the 20-carbon, there is obtained not the 17 tion to convert steroids having at the 17-posi amino compound described in the Julian patent, tion a side chain which includes a carbonyl group but rather a 17-keto compound. This result was at the 20-position, which carbonyl group may be entirely unexpected and makes it possible to de a keto group in a multi-carbon side chain, or grade 20-carbonyl steroids into 17-ketones in a may form part of a 17-aldehydo group, in a sim () simple and inexpensive manner and with rela ple manner into a compound having ketonic oxy tively high yields. gen attached to the 17-carbon. Our process may be represented by way of ex More specifically, it is an object of the present ample by the following graphic formulae: invention to convert A16 compounds of the type CH indicated into 17-keto steroids which are satu 5 rated in ring D. It is known to degrade 17-steroid methyl ketones by reacting the 20-keto group with hy droxylamine and then to Subject the resulting Oxime to a Beckmann rearrangement. This re 20 arrangement results in the formation of a 17 acetylamino Steroid which is difficult to hy drolyze to the 17-keto compound. Such hy drolysis usually results in the intermediate for CE mation of the 17-amino compound which, as de 25 scribed in the patent to Bockmthl, No. 2,212,363, d-oh is then reacted with sodium nitrite to produce the 17-hydroxy derivative, which thereupon is converted to the 17-keto compound by oxidation with chromic oxide in acetic acid solution. This procedure is cumbersome and time-consuming 30 and, in addition, requires intermediate protec - tion of the double bond by addition of bromine which must subsequently be removed, as by treatment With zinc in acetic acid. Aside from In the above formulae - involving a long series of reactions, it is inevitable 35 that the over-all yield of the final 17-keto.com pound is greatly reduced. R represents =O or It has also been Suggested to subject A16-20 Y oximo pregnenes to a Beckmann rearrangement 40 wherein Y is hydroxyl, or groups convertible to with the aid of p-toluene sulfonyl chloride, foll hydroxyl with the aid of hydrolysis, such as ester lowed by treatment with sulfuric acid to produce. groups (like acetoxy, benzoyloxy, etc.), ether the 17-keto compound (Tendick, No. 2,335,616). groups (like methoxy, ethoxy and benzyloxy), This procedure, While it is stated to avoid the chlorine, etc. The starting compounds include formation of the intermediate 17-acetylamido 45 also steroids having a double bond attached to compound, nevertheless requires rigorous reac the 5-carbon, i. e. A- and A5-steroids, and the tion conditions which unfavorably affect the nucleus may also be substituted at other positions, yield of the final product. for example, at the 11- and 12-positions by a hy Finally, it has been suggested (Julian, No. droxyl or substituted hydroxyl group, or by a 2,531,411) to treat 20-oximo pregnane com 50 carbonyl group at the 11-position. pounds which are saturated in the D ring with While the above formulae show starting com p-toluene sulfonyl chloride together with an ". pounds having the carbon skeleton of the preg acetyl acceptor, like ethanolamine, followed by name series, it is within the scope of the invention treatment with sodium hydroxide, which results to employ steroids having only one or more than in the formation of the 17-amine substituted 55 two carbon atoms in the group attached to the steroid...... 17-carbon, Thus the starting compound may be 2,656,364 3 4. a 17-aldehydo steroid, or it may have a 17-side tate oxime in 10 cc. pyridine was treated with chain in which a group is attached to the 20 3 g. of benzenesulfonyl chloride and Subsequently carbonyl group which has two or more carbon treated as described in Example I. In an analo atoms; aad. Such-latter group may be purely hy gous fashion, there was obtained A5-androsten drocarboniini nature or contain substituents-like ) 3(g)'-ol-i'7-one (dehydroepiandrosterone). hydroxyl, ester, ether and other groups, for ex Eacample III ample, of the types above specificially indicated. . In carrying out our invention, the A16-20-car A Solution of 3 g. A16-dehydropregnenolone ace bonyl steroid is first converted into its oxime-in'. tate oxime in 10 cc, pyridine was treated with 3 any Suitable or convenient manner. The oxime" () g-p-toluene sulfonyl chloride, the temperature is then reacted with a sulfonic acid, preferably of the mixture-being kept below 5°. After stand in the form of its chloride, and the reaction-mass: ing for 3 hrs. atroom temperature, the reaction is then heated to effect a rearrangements and," mixture" was treated with 30 cc. aniline and splitting, resulting in the production of the 17 heated-on-the-steam bath for 1 hour. There was keto steroid. To facilitate the rearrangement 15 then added 20 cc. methanol and 10 g. sodium and splitting, the reaction according to the in hydroxide, and the mixture steam distilled un vention takes place in the presence of a con tif no more organic bases were distilled over. pound capable of binding an acyl group,that is. The crude dehydroepiandrosterone was removed of a basically acting organic compound. These by filtration. compounds include monohydrics, and polyhydric 20 Eacample: IV alcohols, including-glycols (such as methanol, ethanol, ethylene:glycol, glycerol, etc.) and pri 3 grams of the p-toluene sulforiate of 6-des: nary and secondary aliphatic-and-cyclic amines, hyaropregnieriolone acetate oxime was treated like butylamine, aniline, etc. The-amines may with 10 g. of ethylenediamine and heated on the be substituted by other groups - like. hydroxyl. steam bathi for 3 hours: Methanol was added, groups, assin-the case-of-alkylolamines, such as: and the solution steam distilled. The crystall." ethanolamine-and diethanolamine. lized dehydroepiandrosterone, which was r The -sulfonic-acid or its-chloride-are-preferably moved by filtration, could be purified by 'crystal aryl-sulfonic acids- or chlorides, such as-benzene. lization from aqueous methanol. Sulfonic acid chloride, p-toluenes, sulfonic acid. 30 Ecamples W. - - chloride etc. . . . --- It will be-evident from the foregoing that in pregnadien-32b-dióries: carrying out the processes of the present inven the Gppeniater oxi tion there are directly obtained 17-keto steroids tion of 16-dehydropregeneolone oxime) in 25 cc. Without the necessity for employing a chromic pyridine was treated with 4g. p-toluene sulfonyl acid oxidation, as described in the Bockmühl chloride, and allowed to stand at room tempera patent above referred to: nor is any protection ture for fourt hiours. The excess-pyridine was of a nuclear double bond required as the inter removed in vacuo; and the residue refluxed with mediate is not subjected to an "oxidation reac 10 cc. benzene and 10cc. 3. tion. It will be seen further that our process 4 hours: After steam distillati eliminates the difficult step of hydrolyzing an 3,17-dione was collected by filtration: acylamido steroid, as in the process of the Ten We claim: . ------dick patent; while the direct production of the 1: Process for the manufacture of 17-keto 17-keto compound eliminates the additional re steroids; which comprises reacting a A16-20-oxino' actions that would be required to convert the 17 iroit with a member of the group consisting amino group of the process of the Julian patent 45 acids and sulfónic acid halides; and irito ketonic oxygen. ° rearrangement of the resulting suli The invention Will be furtheir described in the ester of the oxime to a 17-ketosteroid: following -examples which are presented for pur by heating the saine-in-the-presence of a basical poses of illustration only and not as indicating ly acting organic compound: the Scope of the invention: 50 steroids,2:... Process which for comprises the manufacture reacting-a-A1620-oximo of 17-keto: Eacample I steroid with a-member of the group consisting of sulfonic acids and their chlorides, and eff A solution of 3 grams of $A516-piegiadien-3-(B). ing arearrangement of the resulting sulfonic ac: ol-20-one acetate oxime (16-dehydropregneno 55 ester of the oxime to a 17-ketosteroid by heating' lone acetate oximie) in 10 cc. of pyridine was the same in the presence of an alcohol. . . . treated with 3 g. of p-tolene sulfonyl chloride, 3. Process for the mai re" of 17-keto the addition being at such a rate as to keep the steroids; which coinipiises' rea A16-26-oximo temperature... below. 40. The mixture was al steroid with a member of the group consisting lowed to stand in the ice-box overnight, then 60 of sulfónicaeids and their chlorides, and effect poured into ice and hydrochloric acid. The pre ing a rearrangement of the resulting sulfonic acid." cipitated-oximino-p-toluene sulfonate was iso ester of the oxime to a 17-keto steroid by heat. lated by filtration and dried. If desired, the ing the same in the presence of a member of product may be further purified by crystallization iroup: consisting of primary and secondary from aqueous acetone, but this is not necessary. 65 The p-toluene sulfonate was added to 10cc. of amines.4. Process according to claim 1 in which- a ethanolamine... and the mixture warmed for 2 A16-20-oximo pregnene is the starting compound. hours on the steam bath, 20 cc. of methanol 5. Process according to a claim 4 wherein the and 5 cc 30% sodium hydroxide was added and pregfene compound is substituted in the 3-posi the mixture steam distilled until all the pyridine 0. tion by a group capable of conversion into hy was removed. The crystallized product, dehy droxyl with the aid of hydrolysis: droepiandrosterone, was removed by filtration. 6. Process; for the manufacture of 17-keto steroids, which comprises reacting', as 3-acyl Ecample II A6-20:oximo pregnerie with a member. of, the?: A. solution of 3-gi A6-dehydropregnenolone :ace. 5 group consisting of Sulfonic acids and their chlo', 2,656,864 5 6 rides, and effecting a rearrangement of the re ment of the resulting sulfonic acid ester of the Sulting sulfonic acid ester of the oxime to a 17 Oxime to a 17-keto group by heating the same in keto steroid by heating the same in the presence the presence of a basically acting organic com of a basically acting organic compound. ' pound. 7. Process for the manufacture of A-17-keto 16. Process for the manufacture of dehydro Steroids which comprises reacting a, A5, 16-20-oximo epiandrosterone which comprises reacting an Steroid with a member of the group consisting of ester of A5,6-pregnadien-3(3)-ol-20-one oxime Sulfonic acids and their chlorides, and effecting a with an aryl sulfonic acid chloride, and heating rearrangement of the resulting Sulfonic acid the formed oximino aryl sulfonate With an al ester of the oxime to a 17-keto steroid by heat 10 kylolamine and with an organic base. ing the same in the presence of a basically act 17. Process for the manufacture of dehydro ing organic compound. epiandrosterone which comprises reacting A16 8. Process according to claim 1, wherein an dehydropregnenolone acetate OXime With p-tol aryl Sulfonic acid compound is employed. uene Sulfonyl chloride, and heating the product 9. Process according to claim 1, wherein the 5 With aniline and With alcoholic alkali. Sulfonic acid is p-toluene Sulfonic acid. 18. Process for the manufacture of dehydro 10. Process for the manufacture of A-17-keto epiandrosterone which comprises reacting A16 steroids which comprises reacting a A16-20 dehydropregnenolone acetate OXime With p-tol oximo-pregnadiene with an aryl Sulfonic acid, and uene sulfonyl chloride, and heating the product effecting a rearrangement of the resulting Sul 20 with ethylene-diamine. fonic acid ester of the oxime to a 17-keto 19. Process for the manufacture of A-an androstene by heating the same in the presence drosten-3,17-dione, which comprises reacting of a basically acting organic compound. A4, 16-pregnadiene-3,20-dione-20-monoxime with 11. Process for the manufacture of 17-keto an aryl Sulfonyl halide and thereafter heating steroids having a double bond attached to the 25 the product with a basically acting organic com 5-carbon, which comprises reacting a A16-20 pound. oximo steroid having a double bond attached also 20. Process for the manufacture of A-andro to the 5-carbon, with an aryl sulfonic acid, and sten-3,17-dione, which comprises reacting A, 16 effecting a rearrangement of the resulting Sul pregnadiene-3,20-dione-20-monoxime with p fonic acid ester of the Oxime to a 17-keto 30 toluene Sulfonyl chloride and then heating the androstene by heating the same in the presence product with a primary aliphatic amine to effect of a basically acting organic compound. rearrangement to A-androsten-3,17-dione. 12. Process according to claim 1, wherein the 21. Process according to claim 1 wherein the sulfonic acid compound is a benzene Sulfonyl heating takes place at approximately steam bath chloride. 35 temperature. 13. Process according to claim 1, wherein the 22. Process according to claim 2, wherein Sulfonic acid compound is benzene Sulfonyl chlo the heating takes place at approximately steam. ride. bath temperature. 14. Process according to claim 1, wherein the 23. Process according to claim 3, wherein the sulfonic acid compound is p-toluene sulfonyl 40 heating takes place at approximately steam chloride. bath temperature. 15. Process for the manufacture of 3,17-diketo steroids which comprises reacting a A6-3,20 EMANUE B. HERSHBERG. pregnenedione-20-monoxime with a member of EUGENE P. OLIVETO. the group consisting of Sulfonic acids and Sull fonic acid halides, and effecting a rearrange No references cited.