Patent GB-500353-A (GB)
Title: Process for the manufacture of steroid compounds
IPC: C07J75/00
Filed: 1937-05-31
Abstract: 500,353. Sex hormones. SCHERING- KAHLBAUM AKT.-CES. May 31, 1937, Nos. 15033, 15034, 15035, 15036, 15037, 15038, 15039, 15040, 15041, and 15042. Convention dates, May 29, 1936, Aug. 6, 1936, Sept. 9, 1936, Sept. 29, 1936, Nov. 5, 1936, Nov. 5, 1936, Nov. 6, 1936, Nov. 6, 1936, Dec. 2, 1936, and Dec. 2, 1936. [Class 2 (iii)] 3-Ketones of steroids which contain in ring A either two double bonds, or a second keto group in ortho position to the 3-keto group are prepared by subjecting 3-ketones of steroids di- or polyhalogeinated in rings A and B of the steroid ring system, and at least monohalogenated in the ring A in one or more stages to the action of such agents as are known to be capable of splitting off halogen hydride as are also capable of binding the halogen hydride produced. The agents used may if desired be such that they simultaneously replace halogen by a residue capable of removal or saponification, in which case the products are treated with agents which will remove the substituted group or cause the saponification thereof. It is essential to the success of the process of the present invention that the agents used should prevent the reaction mixture from becoming acid due to free halogen hydride, in order that the changes which take place may be restricted to ring A. The agents mentioned which are particularly suitable for removing hydrogen halide according to the invention include the alkali, alkaline earth, silver and zinc salts of organic acids such as sodium acetate and potassium benzoate. These compounds are preferably reacted in solution, suitable solvents being those which boil at relatively high temperatures such as butanol and other higher alcohols, and also the acids the salts of which are used for splitting off the halogen hydride such as acetic acid, benzoic acid and isovalerie acid. Other solvents such as dioxane and acetone are sometimes used. Organic bases form a valuable class of agents to remove halogen hydride, and among these pyridine and piperidine have proved particularly suitable. Others however such as quinoline, aliphatic and aromatic amines such as dimethylamine, diphenylamine, and dimethylaniline may also be used. Instead of the above methods for removing hydrogen halide, the following methods may be used, particularly when such steroid ketones are employed as contain a keto group at position-3, and arc polyhalogenated in ring A with one halogen atom at position-2. (1) The replacing of halogen by ester or ether groups with subsequent splitting off of acid or alcohol. (2) The replacing of halogen by hydroxyl with subsequent splitting off of water. (3) The replacing of halogen by ester or ether groups with subsequent saponification and elimination of water. As starting materials for this invention the following classes of compounds may be used : (1) Saturated steroid ketones dihalogenated in ring A, such as 2 : 4-dibromo-cholestanone-3, 4 : 4-dibromo-coprostanone-3, 5- chloro-4-bromo-cholestanone-3, and 2 : 4-dibromo-androstandione-3 : 17. (2) Saturated steroid ketones trihalogenated in ring A and /or B, such as 4 : 5 : 6-tribromocholestanone-3, 2 : 2 : 4-tribromo-cholestanone-3, and 2 : 4 : 4- tribromo-coprostanone-3, (3) Saturated steroid ketones tetrahalogenated in ring A and/or B, such as 4 : 4: 5: 6-tetrabromo-cholestanone-(3). (4) Singly unsaturated steroid ketones polyhalogenated in ring A and/or B, such as 4 : 6- dibromo-#<4:5> - cholestenone - 3. Instead of these compounds of the cholesterol and coprosterol series other corresponding polyhalogenated - compounds of sterols for instance of stigmasterol, sitosterol, phytosterol and cinchol. The halogenated ketones of the degradation products of these sterols may also be used such as the corresponding compounds of the androstane and pregnane series, and also the cholanic acids and their lower homologues the norcholanic and bisnor - cholanic acids. The saturated ketones of steroids dihalogenated in ring A yield (a) doubly unsaturated ketones and/or (b) saturated ortho-diketones. The formation of the latter products is especially promoted by causing the dehalogenating agents to react on the starting materials at relatively high temperature for a fairly long time. One may also produce the acyl compound of the unsaturated oxy-ketone and then hydrolyse. This gives particularly high yields. The saturated ketones of steroids trihalogenated in ring A and/or B yield unsaturated orthodiketones with the intermediate formation of doubly unsaturated enol derivatives. It is particularly essential for the formation of enol esters that the reaction be carried out in neutral medium. The saturated ketones of steroids tetra-halogenated in ring A and /or B yield unsaturated ortho-diketones, as also do the singly unsaturated ketones of steroids polyhalogenated in ring A and/or B. The binding of the hydrogen halide is sometimes assisted by the addition of substances which react with hydrogen halide such as calcium carbonate. In addition to the products referred to above there are produced as by-products in more or less large amounts, certain compounds containing nitrogen. These nitrogen containing compounds separate in crystalline form from the reaction solutions on cooling. On thermal decomposition, these compounds split off the nitrogen containing group. In examples: (1) 2 : 4-dibromo-cholestanone-3 is boiled with potassium acetate in a mixed solvent consisting of toluene and butanol. The reaction product is diluted with water, extracted with ether, and worked up to yield a benzoate which splits off benzoic acid on distillation to give a doubly unsaturated ketone. The second part of this example may, if desired be performed with the enol derivatives of the mono esters of the unsaturated hydroxy ketones instead of with the esters themselves. (2) 2 : 4-Di bromo cholestanone-3 is boiled with potassium acetate in isovaleric acid solution to give an ester which is converted into a doubly unsaturated ketone as in example (1). (3) 2 : 4- Dibromocholestanone-3 is treated as in example (1) under slightly varying physical conditions. (4) 2 : 4-Dibromo-cholestanone-3 is boiled with pyridine to give a compound of the formula C32H49ONBr. This compound on distillation under a very reduced pressure slits up to give an unsaturated ketone. (5) 2 : 4-Dibromocholestanone-3 is boiled with pyridine in excess for a long time to give cholestadienone-3, together with cholestenonyl - pyridinium bromide. The latter is separated due to its insolubility in water. The aqueous mother liquor yields on further treatment a considerable amount of # <1.2 : 4.5>-cholestadienone-3. (6) Dihromo-androstandione is boiled with pyridine to give after the removal of the pyridine in a vacuum, #<1.2> : <4.5>-androstadiendione-3 : 17. A small yield of apyridyl-ketone is also obtained. (7) 2 : 4-Dibromocholestanone-3 is further brominated to give tribromocholestanone, which is then decomposed by boiling with dry pyridine to form an unsaturated pyridine condensation product. (8) The tribromide obtained when cholesterol is oxidized and brominated is added in benzene solution to a boiling alcoholic solution of potassium acetate to give an enol-acetate. This is then saponified by boiling in alcohol solution with concentrated hydrochloric acid. (9) A chloroform-alcohol solution of cholestanone-4 : 5 : 6-tribomide is allowed to stand at room temperature with potassium acetate to give a dibromide which is then boiled with an alcoholic solution of potassium acetate to give an enol acetate. This compound on hydrolysis as in example (R) gives the same unsaturated ortho-diketone. (10) Cholestenone is brominated in ethereal solution to give a dibromide which is converted into the doubly unsaturated enol acetate as described in example (9). From the main mother liquor after several days there is obtained an isomer of the dibromide above with a lower melting point. Like the parent dibromide. this compound may be converted into an enol acetate by boiling with alcoholic potassium acetate. On saponification as described in example (8), a singly unsaturated ortho-diketone is obtained. In a similar manner by halogenation of #<4><:5> unsaturated ketones of other steroids such as progesterone, androstendione, and testosterone the corresponding dihalogenated unsaturated ketones are finally obtained. Complete dehalogenation of these compounds yields more or less misaturated ketones or polyoxo-compounds. (11) 4 : 4 : 5 : 6-Tetrabromo-cholestanono-3 is boiled in butanol solution with potassium acetate to give #<5 : ><6>-cholestendione-3 : 4. (12) 2 : 4- Dibromocholestanone is boiled with potassium acetate in butanol solution to give cholestandione. This can be converted into its enol acetate by treatment with acetic anhydride in pyridine solution, and into a quinoxaline derivative by treatment with ortho phenylene diamine in alcoholic solution. (13) Cholesterolhydrochloride is treated in glacial acetic acidbenzene solution chromic anhydride to convert it into chlorocholestanone, which is then brominated to form chlorobromocholestanone This is then transformed into either 3 : 4-, or 3 : 6-cholestandione by treatment with potassium acetate, the isomer obtained being determined by the reaction conditions. Alternatively, the chlorobromocholestanone may be transformed into an alpha-#-unsaturated monobromide as an intermediate product before conversion into the diketone. Similar reactions may also be carried out with androstane compounds. (14) 2 : 4-Dibromoandrostandione is treated with potassium benzoate in butanol-toluene solution to give an unsaturated benzoate, which is heated in a high vacuum to give an unsaturatcd diketone. Instead of the dihalogenated androstandione, there may be used the androstanol-17-one-3, the 17-alkyl-substituted compounds and the 2-, or 4-mono-esters of the unsaturated 2-, or 4-hydroxy-androstenol-17-ones-3, or their 17- alk