DE871450C - Process for the preparation of ketones of the cyclopentanopolyhydrophenanthrene series - Google Patents

Description

Process for the preparation of ketones of the cyclopentanopolyhydrophenanthrene series It has been found that ketones of the cyclopentanopolyhydrophenanthrene range can be obtained can get if you have carboxylic acids or such acid derivatives of this series, the contain an amide, nitrile, nitrile oxide, halogen, anhydride or salt group, either with suitable organometallic compounds to form ketones or with organic ones Converts metal derivatives derived from compounds with active methylene groups, and the condensation products obtained cleave and decarboxylate and, if one of i7-oxy-, i7-acyloxy- or 17-alkoxycarboxylic acids of the cyclopentanopolyhydrophenanthrene series or their acid derivatives mentioned, on the reaction products obtained directly afterwards or after further reactions, dehydrating, acidic or alcohol-releasing Allow agent to act and hydrogenated double bonds formed or, if one of Nitrile oxides derCyclopentanopolyhydroplienanthrenreihe has started, the resulting Ketoxime saponified.

The starting materials are generally saturated or mono- or polyunsaturated compounds of the cyclopentanopolyhydrophenanthrene series which have carboxyl groups or carboxylic acid derivative groups in side chains, such as unsubstituted or substituted carboxamide groups, also nitrile, carboxylic acid halide, anhydride or salt groups, use, e.g. B. those of the type of Etiocholans, Pregnans, Oestrans, Hydrooestrans or their stereoisomers, homologues and partial dehydrogenation products. The carboxylic acid residues can otherwise adhere directly to the ring structure, e.g. in position 17 or 3, or from it e.g. B. separated by one or more carbon atoms. Such carboxylic acid derivatives are, for. B, by gradual or radical breakdown of sterols, bile acids, genins of cardiac glucose or by building up, starting from ring ketones and the like., Accessible. In addition to the carboxylic acid residues, they can of course also contain other substituents, e.g. B. substituted or unsubstituted hydroxyl, carbinol, amino or hydrocarbon groups, also halogen atoms, ring keto groups and especially their enol derivatives, such as enol esters and ethers. In the latter case, the enol groups can be converted back into keto groups after the reaction. In particular, one also starts from compounds which carry a carboxyl group or a carboxylic acid derivative group and a hydroxyl, acyloxy or alkoxy group on the same ring carbon atom. As starting materials are mentioned in particular z. B. saturated and unsaturated halides, nitriles, A.mide (also substituted), anhydrides of etiocholanic acids, such as 3-oxY-, 3-keto- and or -i7-oxy-etio-cholanic acids, 3, ii-diketo - Or 3-KetO-II-OxY- and or, or -i7-oxy-ätio-cholansäuren, also corresponding compounds of bisnorcholansäure-, the Cholani7-acetic acid-, the nor-cholansäure-, the 3-Carboxyätiocholansäurreihe, analogous carboxylic acids of Oestrone or hydrooestrone series or their derivatives, such as esters and ethers, enol esters and enol ethers, and their stereoisomers, in particular the compounds which differ by configuration change at carbon atoms 3, 5, - 9, 11, 17 and / or 2o.

Organometallic compounds are understood as meaning saturated and unsaturated Compounds of metals such as alkali metals, magnesium, zinc, cadmium, mercury, Copper, aluminum or tin, with substituted or unsubstituted alkyl, Cycloalkyl #, aralkyl or aryl radicals, for example metal hydrocarbon compounds, such as lithium methyl, sodium benzyl, phenyl potassium, acetylene potassium, zinc, magnesium and mercury dialkyls, aluminum trialkyls, tin di- and tetraalkyls, and also organic ones Metal halides, e.g. B. of calcium, mercury, tin and lead, in particular but those of magnesium and zinc, such as methyl, ethyl, allyl, vinyl, acetylene, Methyl ether, cyclohexyl, phenyl or benzyl magnesium or zinc halides. Of organic metal derivatives, which differ from compounds with active methylene groups, such as ß-dicarboxylic acid derivatives, ß-ketocarboxylic acid derivatives, ß-diketones, or z. B. can also be derived from their derivatives monosubstituted on the active methylene called the metal derivatives of malonic esters, malonitrile, malonamide, analogues # cyanoacetic acid and acetoacetic acid derivatives, of acetylacetone and their substitution products and homologues containing e.g. B. alkali metals, copper, aluminum and the like.

Since the reactivity of the various organometallic compounds and also of the carboxylic acids or their various derivatives is very different, so that ketones are actually obtained, the appropriate reactants and suitable reaction conditions, as they are known per se (see e.g. H ou b en-Weyl, Methods of Organic Chemistry, 2nd ed., Vol. 4, pp. 777ff. And 897ff.). So you get z. B. from nitriles or acid amides with Grignard compounds readily in good yields of ketones. Starting from acid anhydrides and carboxylic acid alkali salts, this is also the case with a corresponding procedure. When working with acid halides, it is recommended e.g. B. not to use much more than calculated amounts of the magnesium compounds or then to use the somewhat less reactive zinc compounds to stop the reaction at the ketone stage. Here z. B. substituted or unsubstituted alkyl, aralkyl or arylalkali compounds are used. Finally, acid halides can be reacted with metal derivatives of compounds with active methylene groups and the condensation products obtained in this way can be cleaved and decarboxylated in a manner known per se, that is to say, for. B. saponify, subject to ketone or acid cleavage. Instead of using pre-formed organometallic compounds or organic metal derivatives derived from compounds with active methylene groups, it is also advisable to allow the individual components to act on the carboxylic acids or acid derivatives, especially in cases where the metal compounds are difficult to access or are unknown as such are, for example in the case of chloromethyl ether, vinyl bromide and the like.

The reaction mixtures are worked up by known methods. So z. B. when using magnesium or zinc compounds mostly primary The resulting metal-containing addition compounds are decomposed with dilute acids.

The process according to the implementation of acid chlorides with z. B. methyl zinc iodide (example i), zinc methyl (example 2) and sodium malonic ester (example 3) can be formulated as follows: If nitrile oxides are used as the starting point, the resulting ketoximes are also converted into ketones by the somewhat more energetic action of acids. If you finally have i7-oxy-, i7-acyloxy- or 17-alkoxycarboxylic acids or. If acid derivatives are used, the reaction products obtained are allowed to act on the reaction products obtained immediately afterwards or after further reactions, and agents which split off acids, acids or alcohols are allowed to act, and the double bonds formed are hydrogenated. Such a subsequent hydrogenation can of course, for. B. also take place, if one started from the outset from 16, 17-unsaturated compounds.

In addition to carboxyl groups and their derivatives, others can of course also Substituents with the organic metal compounds in reaction. So react Grignard compounds e.g. B. also with hydroxyl, amino, acyloxy, keto, aldehyde and heavier also with halogen groups. In the first cases, however, when dismantling of the magnesium addition products again easily unchanged or only saponified Regaining substituents. Existing ketones can, if not implemented is desirable by intermediate conversion into their enol derivatives such as enol esters or ether, protect.

The resulting ketones of the cyclopentanopolyhydrophenanthrene series are therapeutically very valuable compounds or can be converted into such. Some of them are known. Thus, according to Example 3, the corpus luteum hormone progesterone is obtained. Up until now, this compound had to be obtained either from the relatively expensive stigmasterine through a long series of operations or from the pregnanediol, which is present in sparse amounts in pregnant women’s urine. In contrast, according to the new process, cheap cholesterol can be used as the parent substance, which is of crucial importance for the economical production of progesterone.

Example i 4.8 parts of A "6-3-acetoxy-17-benzoxy-ethio-cholenic acid are suspended in 7 parts of absolute benzene and 50 parts of thionyl chloride are added. The mixture is heated in the water bath until the evolution of gas has ceased and the solution is then evaporated to dryness in vacuo and the acid chloride obtained in this way is dissolved in absolute toluene. A solution of 2.1 parts of methylzinc iodide in toluene, prepared in the usual way, is then added with cooling and left to stand for a short time at room temperature. Dilute hydrochloric acid decomposes and the toluene layer, after dilution with ether, is washed with dilute hydrochloric acid, dilute soda solution and water. After drying over sodium sulfate, the ether solution is evaporated in vacuo and the residue is sublimed in a high vacuum at about 180 ', whereby benzoic acid is split off. The sublimate is dissolved in ether, the ethereal solution washed with dilute soda solution and water and evaporated Etat des d5,6-.d16,17-pregnadienol- (3) -one- (2o) can be partially converted to the acetate des, d5,6-pregnenol- (3) - without further purification with a nickel catalyst prepared according to R ane y. ons- (2o) hydrogenate. For this purpose it is dissolved in 80 parts of 930% ethyl alcohol and, after the addition of 1.5 parts of Raney nickel, is shaken with hydrogen at Zirnmer temperature until 1 mol of hydrogen is absorbed. The solution is then filtered and evaporated and the residue is recrystallized from dilute alcohol. In a yield of 35 %, the acetate of A ', l-pregnenol- (3) -ODS- (20), which crystallizes in needles and melts at 147', is obtained, and from it by saponification the A5,6- which melts at 193 ' Pregnenol- (3) -one- (2o) of the formula .%. In parts of methylzinc iodide, the reaction can also be carried out with dimethylzinc. If ethyl zinc iodide, dipropyl zinc and the like are used, homologs of pregnenolone are obtained. The reduction of the 16, 17 double bond can also be carried out with other catalysts, further z. B. perform with zinc and glacial acetic acid. Instead of the acid chloride, other halides or z. B. also use acid amides, anhydrides or salts.

Instead of aceto.xy-benzoxy-ethio-cholenic acid, it is derived from 3-enol acetate the d4 "'- 3-keto-etio-cholenic acid started out, one arrives at the conversion of it Acid halides with z. B. Dimethylzinc and saponification directly to A4,5-Pregnendione- (3.20) [Progesterone].

EXAMPLE 2 A solution of 1 part of dimethylzinc in 2 parts of benzene is added dropwise with cooling and in a nitrogen atmosphere to a solution of 10 parts of A5'6-3,17-diacetoxy-ethiocholenic acid chloride in 450 parts of benzene. A violent reaction can be observed with every drop. You swirl around for a short time, then, first carefully, add about 500 parts of water, acidify with hydrochloric acid and ether out. The ether solution is carefully washed with sodium hydroxide solution, dried and evaporated. The residue is recrystallized from acetone or, in the case of larger batches, from M ' ethanol and the d5'6-3,17-diacetoxy-pregnenone- (2o) of the formula is obtained in about 550% yield With alkaline saponification it provides the free A5'6-I7-OxY-Pregnen01- (3) -On- (20).

Instead of dimethyl zinc one can also use methyl zinc halides, or the acid halide can be reacted with metal dialonic esters or acetacetic esters and then hydrolyze and decarboxylate. If you use organic metal compounds, which introduce higher hydrocarbon residues, such as diethyl zinc, benzyl zinc bromide, Sodium ethyl malonic ester and the like, this leads to homologues of oxy-pregnenolone.

EXAMPLE 3 A Bellzol solution of 3.5 parts of d4,5-3-ketoethio-cholenic acid chloride (prepared for example by reaction of the free acid with thionyl chloride) is added, first carefully, to an absolutely alcoholic solution of three parts sodium malonic ester in benzene solution and in the presence of calcium carbonate, filtration and evaporation of the solvent). After the first violent reaction is over, the mixture is heated to boiling for a few more hours with stirring, then the bulk of the alcohol is evaporated off in vacuo, the residue is mixed with water and extracted with ether. The ethereal solution is washed with bicarbonate solution and water, evaporated and the residue obtained is the crude A4 "'- 3-keto-pregnenon- (2o) -2i-dicarboxylic acid ester. This is saponified with 20% strength for one hour Mentioned alcoholic alkali, then the solution is acidified, precipitated with water and extracted with ether. The ethereal solution is washed with water, dried and evaporated. The residue is sublimed in a high vacuum (o, ooo5 mm) at about 115 'and or or over the very poorly soluble disemicarbazone purified and in 400 /, iger yield pure progesterone of the formula the iii dimorphic forms of the melting points i2o and igg 'crystallize.

Instead of the 3-keto-etio-cholenic acid itself, it is also possible to use its enol derivatives, like enol esters and ethers. If, on the other hand, one starts from 3-acyloxy-etio-cholenic acid halides off, then one arrives analogously to AI, 6-pregnenol- (3) -one- (2o).

Instead of the sodium malonic ester, for. B. Alkali compounds of Malonitrile, Malonarffid, cyanoacetic acid and acetoacetic acid derivatives use Find. In the latter case, the condensation product then undergoes acid cleavage subjected, decarboxylated and thus also obtained progesterone. Will however carried out the ketone cleavage, one arrives at an unsaturated triketone the Cyclopentanopolyhydrophenanthrene rule with a ß-diketone group in the side chain. Tetraketones are obtained if metal compounds are used to react with the acid halide of acetyl acetone or its homologues are used.

Saturated compounds are also accessible in an analogous manner, e.g. B. those of the 3-epi-oxy-allopregnanon (2o) series.

Claims (2)

PATENT CLAIMS: i. Process for the preparation of ketones of the cyclopentanopolyhydrophenanthrene series, characterized in that carboxylic acids or acid derivatives of this series which contain an amide, nitrile, nitrile oxide, halogen, anhydride or salt group, either with suitable organometallic compounds to form ketones or with organic metal derivatives which are derived from compounds with active methylene groups and cleave and decarboxylate the condensation products obtained and, if 17-oxy-, 17-acyloxy- or 17-alkoxycarboxylic acids of the cyclopentanopolyhydrophenanthrene series or their acid derivatives are used as the starting point reaction products obtained directly afterwards or after further reactions allows water-, acid- or alcohol-releasing agents to act and hydrogenating double bonds or, if nitrile oxides of the cyclopentanopolyhydrophenanthrep series are used, the ketoximes formed are saponified. 2. The method according to claim i, characterized in that the organometallic compounds used are substituted or unsubstituted, saturated or unsaturated metal alkyls, aralkyls or aryls. 3. Process according to claim i, characterized in that organic metal halides, in particular of magnesium or zinc, are used as organometallic compounds. 4. The method according to claim i to 3, characterized in that instead of preformed organometallic compounds or organic metal compounds which are derived from compounds with active methylene groups, the individual components can act on the carboxylic acids or acid derivatives. Attracted publications -Hoppe-Seylers Zeitschrift für Physiologische Chemie, Vol. 230, pp. 185 ff -; Dutch Patent No. 39,469. French patent specification No. 820 537.