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United State S Patent Office Patented Dec 3,014,931 United State s Patent Office Patented Dec. 26, 1961 2. of 19-nor-4-pregnene-3,20-dione; the yields of the prod 3,0i4,931 10-CARBOXY.A4ANCROSTENES AND PROCESS ucts are no more than 6.2% and 3.3% relative to the FOR THE PRODUCTiON THEREOF starting steroids, respectively. Thus this process is not Masamoto Nishikawa, Nishinomiya, and Hikoichi Hagi suited for any practical purpose. wara, Oyodo-ku, Osaka, Japan, assigaors to Takeda The present invention is directed to the embodiment Pharmaceutical industries, Ltd., Osaka, Japaa of practical means for the preparation, on an industrial No Drawing. Filled Mar. , 1960, Ser. No. 12,001 scale, of the A4-3-oxo-19-norsteroid compounds. Briefly Claims priority, application Japan Sept. 30, i958 stated, this means-according to the invention- involves 16 Claims. (C. 260-397.) essentially the conversion of initial A-3-oxo-19-oxo (or 0 hydroxy)-steroid compounds into the desired A-3-oxo The present application is a continuation-in-part of co 19-norsteroid compounds. A feature of the invention is pending application, Serial No. 841,953, filed September that the starting steroid compounds can themselves be 24, 1959, now abandoned. prepared on an industrial scale and in good yield by The present invention relates to the preparation of subjecting the corresponding 19-unsubstituted A-3-oxo A-3-oxo-19-norsteroid compounds. Features of the pres steroid compound to biological oxidation with a micro ent invention which contribute to its feasibility for use in organism of the genus Corticium (after the manner de the industrial production of A-3-oxo-19-norsteroid com scribed in “Chemical and Pharmaceutical Bulletin,' vol. pounds are inter alia (a) the fact that easily accessibie 6 (1958, pp. 226-228), and if desired oxidizing the re compounds are employed as starting materials and (b) sulting A-3-oxo-19-hydroxysteroid compounds with an that the reaction conditions are milider than those hereto 20 oxidizing agent such as chromic anhydride in a suitable fore employed in the manufacture of A-3-oxo-19 solvent such as acetic acid, pyridine or acetone (after the norsteroid compounds. Some of these compounds have maner described in the aforementioned papers by A. S. been known as sex hormones, while others have been Meyer and by G. W. Barber et al.). used as significant intermediates in the preparation of The means provided by the present invention for sex hormones, etc. achieving the desired object are representable by the foll Aš-3-oxo-19-norsteroid compounds have lowing scheme: . - - - - been prepared as follows: heretofore A.35(0)-3-alkoxy-19-norsteroid compounds are re CHO duced to A3,5(10)-3-alkoxy-19-norsteroid compounds by the Birch method, and then the latter are converted into the 30 A-3-oxo-19-norsteroid compounds directly or through A5(0)-3-oxo-19-norsteroid compounds. This can be rep resented by the following scheme (R represents an alkyl group): 35 -3 Os (III) (O-O 40 N H 45 Os (V) As is evident from this reaction scheme, the desired This process, however, entails disadvantages such as re A-3-oxo-19-norsteroid compounds can be prepared di quiring complicated steps for preparing the starting ma 50 rectly from A-3,19-dioxosteroid compounds (procedure terial, and the process itself is very intricate. A, I->V). They can also be prepared from A-3-oxo The A-3-oxo-19-norsteroid compounds can also be pro 19-hydroxy (or oxo)-steroid compounds through A-3- duced by the elimination of formaldehyde from 19-hy. oxo-10-carboxy-19-norsteroid compounds; or from A-3- droxy-A-3-oxosteroid compounds, according to the fol oxo-10-carboxy-19-norsteroid compounds directly or lowing scheme: 55 through A5(0)-3-oxo-19-norsteroid compounds (proce CEO dures B). This aspect of the invention thus also pro vides means for preparing A5(10)-3-oxo-19-norsteroid com /N C H pounds from A-3-oxo-10-carboxy-19-norsteroid com pounds. Novel intermediates for synthesizing A4-3-oxo A B 60 19-norsteroid compounds are also incidentally provided. O Dealing first with the "B" procedural aspect of the in TN/N/ vention, various alternatives are possible: This process, however, is only of theoretical interest, giv Thus, A-3-oxo-19-hydroxy (or oxo)-steroid compounds ing only very poor yields. Thus the reaction between (I or II) are first oxidized with an oxidizing agent to A 13.6 milligrams of 19-hydroxy-4-androstene-3,17-dione 65 3-oxo-10-carboxy-9-norsteroid compounds III, and then and potassium hydroxide in ethanol see "Experientia,” the products are heated under atmospheric or reduced vol. 11, p. 99 (1955), report by A. S. Meyer), yielded pressure to convert them into A5(10)-3-oxo-19-norsteroid 0.75 milligram of the corresponding 19-norsteroid, 19 compounds IV and finally treated with a strongly acid or nor-4-androstene-3,17-dione, as a byproduct, and the same strongly alkaline agent to obtain the final products V. reaction with 30 milligrams of 19-hydroxy-4-pregnene 70 Or, the first intermediates III can be converted directly 3,20-dione see “J. Org. Chem...' vol. 20, p. 1253 (1955), into the final products V by heating with a strongly acid report by G. W. Barber et al. gave only 0.9 milligram or strongly alkaline agent. - 3,014,931 3 4. The starting steroid compounds may belong to the tion of a strongly acid or strongly alkaline agent. This androstane-, pregnane-, cholanic acid- or cholestane reaction may preferably be carried out in a solvent con series, but must have a double bond between the positions taining a strongly acid or strongly alkaline agent, and is 4 and 5, an oxo group at the 3-position, and a hydroxyl accelerated by heating. The acid agent may be a mineral or oxo group at the 19-position. Thus, for example, 19 acid such as hydrochloric or sulfuric acid, or an organic hydroxy - 4 - androstene-3,17-dione, 19 - hydroxy-4- sulfonic acid, or a sulfonic acid resin, for instance, and pregnene - 3.20 - dione, methyl 19 - hydroxy - 4 - andros the alkaline agent may be oxide or hydroxide of alkali or tene - 17B - carboxylate, 19 - oxo - 4 - androstene - 3,17 alkaline earth metals, for instance, the solvent employed dione, 19-oxo-4-pregnene-3,20-dione, methyl 19-oxo-4- in this reaction may, for example, be water, a lower androstene-17B-carboxylate, and so on may all be em fatty alcohol such as methanol and ethanol, a lower fatty ployed as starting materials in the “B” aspect of this in ketone such as acetone and methyl ethyl ketone, or a vention. (As the reactions in the processes of this inven lower fatty ether such as diethyl ether and dioxane and tion are all effected under considerably mild conditions their mixtures. and are all concerned with only the A-ring of the steroid In the more direct and therefore more advantageous nucleus, the substituents or unsaturated bonds on the 5 'A' form of the invention: B-, C- and D-rings or on side chains are not affected CO at all by the reactions, and the substituents do not exert any obstructive influence on the reactions either. The C H. C. starting steroid compounds may thus have oxo-, hydroxyl or lower alkyl groups or halogen atoms at possible posi 20 A - A B tions, and moreover they may have double bond(s) on r. r the B-, C- or D-ring or on a side chain). 0-\/\/ o-N/ In the first step of the “B” form of this invention, the the starting material may again belong to the androstane starting steroid compounds (I, II) are converted into pregnane- or cholanic acid-series. More concretely, 19 A-3-oxo-10-carboxy-19-norsteroid compounds III through 25 oxo - 4 - androstene - 3,17-dione, 178 - hydroxy - 19 oxidation. The oxidation can be effected with any ox oxo-4-androsten-3-one or its 17a-lower alkylated deriva idizing agent capable of oxidizing the methylol or tives, 19-oxo-4-pregnene-3,20-dione, 17a-hydroxy-19-oxo formyl group to the carboxyl group. As the oxidizing 4 - pregnene -3,20 - dione, 21 - hydroxy - 19 - oxo - 4 agent, there may, for example, be employed chromium pregnene - 3,20 - dione, 17a,21- dihydroxy - 19 - oxo-4- trioxide, permanganic acid, nitric acid, halogenic acids or 30 pregnene-3,20-dione, 3,19-dioxo-4-androstene-7-carbox their salts, lead peroxide, silver oxide, cupric oxide, ferric ylic acid and its lower alkyl esters and so on may all be compounds, hydrogen peroxide and organic peroxides. employed as the starting material in this embodiment of The oxidation may conveniently be carried out in a suit this invention. These starting steroids can be prepared able solvent in accordance with the kind of oxidizing on an industrial scale, as hereinbefore described. agent used and of the starting material employed. The 35 The reaction of this phase of the present invention can Solvent may be Water, lower fatty alcohols such as meth be effected by allowing any of the above starting steroid anol and ethanol, lower fatty ketones such as acetone and compounds to react with an acid or an alkali agent. The methyl ethyl ketone, lower fatty ethers such as dioxane alkali agent may be selected from such strongly alkaline and diethyl ether, and aromatic hydrocarbons such as agents as alkali metal oxides, alkali metal hydroxides, al benzene and toluene and petrolic solvents, for instance.
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