DE1092013B - Process for the production of methyl steroids - Google Patents

Description

Method of Making Methyl Steroids The present invention relates to a process for the preparation of previously not described 6,16a-dimethylpregnene derivatives. These new steroids have a significantly increased progesterone effect or Can be used as intermediates for the production of chemotherapeutically interesting Find corticoid analogs use.

The process according to the invention uses 3,5-cyclo-16-pregnen-6-ol-20-one as starting material and 6-methyl-5,16-pregnadien-3β-ol-20-one. The new synthesis proceeds according to the reaction scheme. The individual process stages are known per se using customary methods Way done.

The invention accordingly relates to a method of production of methyl steroids, which consists in being in a manner known per se 3,5-Cyclo-16-pregnen-6-ol-20-one (I) by treatment with a mild oxidizing agent converts this diketone (II) into 3,5-cyclo-16-pregnen-6,20-dione (II) by Grignardation with methyl magnesium bromide or iodide in 3,5-cyclo-6,16a-dimethyl-pregnan-6-ol-20-one (11I) transferred, the latter (III) by the action of a mixture of acetic acid or formic acid and a small amount of a strong acid, preferably sulfuric acid, rearranged to the 6,16a-dimethyl-5-pregnen-3ß-ol-20-one-3-acetate (IVb) or -3-formate (IVc) and optionally this compound (IVb or IVc), optionally after the previous one Saponification of the ester group in position 3 by treatment with a mild oxidizing agent or by exposure to a culture of Flavobacterium dehydrogenans or one thereof obtained enzyme converts into 6a, 16a-dimethyl-4-pregnen-3,20-dione (V), or that Compound I can be obtained in a manner known per se by Grignardation with methylmagnesium bromide or iodide converted into 3,5-cyclo-16a-methyl-pregnan-6-ol-20-one (Ia), the latter by treatment with a mild oxidizing agent to 3,5-cyclo-16a-methyl-pregnane-6,20-dione (II a) is oxidized, this diketone (II a) by Grignardation with methylmagnesium bromide or iodide or by reaction with alkali methyl, preferably lithium methyl, in Compound III converted and the latter, as indicated, in connection IVa, IVb or IVc and this optionally converts into compound V, or that is known per se Assign 6-methyl-5,16-pregnadien-3ß-ol-20-one (III a) by Grignardation Methylmagnesium bromide or iodide converted into compound IVa and the latter optionally, as indicated, converted into compound V.

The Grignardation of I, II, Ha or III a succeeds under the usual Conditions of a Grignard reaction with methyl magnesium bromide or iodide. Included For I, 1I and III a it has proven to be advantageous to use the ethereal Grignard solution to submit and the steroid in a somewhat higher-boiling inert solvent, such as B. toluene to be added. The Grignardation can then be carried out in good yield are by distilling off the ether and the reaction under reflux in the higher boiling solvent is carried out. With connection II takes place simultaneously 1,4-addition with introduction of the 16a-methyl group and Grignardization of the 6-keto group.

Compound II a can also by treatment with alkali methyl, z. B. Lithium methyl, can be converted into compound III. This procedure is less economical than the usual grignarding. For the oxidation of the 6-hydroxyl group the compounds I and Ia can be, for. B. chromic acid or a mixture of chromic acid and use pyridine or acetone.

The rearrangement of compound III to compound IV is carried out Treatment with formic acid or acetic acid in the presence of a small amount of one strong acid, preferably with a sulfuric acid-acetic acid mixture. It it is sufficient to leave the reaction mixture to stand overnight at room temperature. the Work-up can be done by extracting the steroid IV formed from the reaction mixture be carried out with chloroform. Instead of sulfuric acid, you can also use a other strong acids such as B. perchloric acid. In this implementation forms compound IVb or IVc.

Compound IIIa can be as usual with methylmagnesium bromide or -Iodide grignard. 1,4-addition takes place with formation of compound IVa.

IVa, IVb or IVc can be converted into compound V by treatment with a culture of Flavobacterium dehydrogenans or an enzyme produced therefrom. As a nutrient solution you can z. B. an aqueous solution of 10 /, yeast extract, which is adjusted with a phosphate buffer according to Sörensen to about p $ 6.8, use. A 24-hour shaking culture of Flavobacterium dehydrogenans is allowed to grow for about 10 hours at 28 ° C. with vigorous stirring and aeration, and then the steroid IVa, IVb or IVc is added. Incubation and aeration then continue for about 6 to 8 hours. The course of the reaction can be followed by measuring the UV spectrum. Compound V can be extracted from the culture solution with chloroform.

IVa or IVc can be chemically, e.g. B. by Oppenauer oxidation, be converted into V.

If the oxidation is carried out with a mixture of chromic acid in pyridine or in acetone or with chromic acid alone, it is necessary to saponify the 3-hydroxyl group of IVb or IVc to form IVa.

If you want to carry out the last stage chemically, is it z. B. advantageous, compound III with a mixture of formic acid and one convert a small amount of sulfuric acid into the formate IVc and this subsequently to be oxidized to V under the conditions of an Oppenauer oxidation. You save on this method, the otherwise necessary saponification of the 3-ester group.

The 3,5-cyclo-16-pregnen-6-ol-20-one (I) required as starting material can be obtained from 5,16-pregnadien-3ß-ol-20-one (accessible as a technical product from diosgenin) by treatment with p-Toluenesulfonyl chloride in pyridine and reaction of the 5,16-pregnadien-3ß-ol-20-one-3-tosylate obtained with basic agents (cf. British Patent 801 794).

The 6-methyl-5,16-pregnadien-3β-ol-20-one also used as starting material can be obtained by known methods by breaking down diosgenin (cf. D. Burn et al, journal of the Chemical Society, London, 1957, p. 4092).

6a, 16a-dimethyl-4-pregnen-3,20-dione is said to be a drug with progesterone effects in human medicine and as an intermediate in the manufacture of chemotherapeutic products more effective corticoid analogs can be used. The intermediate products 3,5-Cyclosteroids can be used as a means of combating mental illness.

6,16a-Dimethyl-5-pregnen-3ß-ol-20-one or its 3-acetate or 3-formate (IVa to IVc) can be used as anabolic substances and are also important intermediate products for the production of corticoids. Example 1 a) 20 g of chromic anhydride are mixed in the cold with 200 ml of absolute pyridine, and a solution of 20 g of 3,5-cyclo-16-pregnen-6-ol-20-one (I) (is shown for this mixture according to the method of British patent specification 801 794) in 100 ml of pyridine. After standing for 6 hours at room temperature, the mixture, which has meanwhile turned deep dark brown, is poured into about 500 ml of boiling benzene, refluxed for 10 minutes, then suction filtered over a thin layer of silica gel and the filter residue washed thoroughly with hot benzene. The filtrate is neutralized with dilute sulfuric acid and then with sodium hydrogen carbonate solution, dried and evaporated to dryness. The residue consisting of 3,5-cyclo-16-pregnen-6,20-dione (II) is purified by recrystallization from methanol. Yield: 700/0 of theory; Mp 184 ° C; [a] D = + 94.5 ° 1 (chloroform). b) In 1 l of absolute ether, a Grignard solution is prepared from 23 g of magnesium and 59 ml of methyl iodide (= 132 g); 20 g of compound II, dissolved in 450 ml of toluene, are added; the ether is distilled off on the steam bath and the remaining toluene solution is heated overnight on the steam bath. Working up is carried out by column chromatography, since a bisnorcholan derivative is also formed in addition to the desired 3,5-cyclo-6,16a-dimethyl-pregnan-6-ol-20-one (III). Compound III is obtained by elution with benzene and can be obtained in pure form by recrystallization from acetone with a melting point of 143 to 145 ° C; XD = -! - 86.1 (chloroform). The unwanted by-product has a melting point of 202 to 203 ° C.

c) 6 g of compound III are dissolved in 120 ml of glacial acetic acid; 1 ml concentrated Sulfuric acid is added (it turns violet after a short time) and the mixture was allowed to stand overnight at room temperature. It is poured in water extracted with chloroform, the chloroform solution with sodium hydrogen carbonate solution neutralized, dried and evaporated. The remaining 6,16a-dimethyl-5-pregnen-3ß-ol-20-one-3-acetate (IVb) is recrystallized from methanol; M.p. 136-137 ° C. By usual treatment with a saponifying agent, e.g. B. by the action of sodium hydrogen carbonate, compound IVb can be converted into the free alcohol IVa; Mp. 168-169 ° C.

d) 4 g of compound IVa are dissolved in 140 ml of toluene; 40 ml of cyclohexanone are added and about 40 ml from the mixture to remove any moisture distilled off. Then a solution of 3 g of aluminum isopropoxide in 15 ml Toluene was added and the mixture was refluxed for 2 hours. After adding 150 ml of water and 1 ml of glacial acetic acid is steam distilled for 6 hours, then the aqueous residue extracted with chloroform and evaporated the chloroform solution after drying. That remaining 6a, 16a-dimethyl-4-pregnen-3,20-dione (V) is recrystallized from ether; Mp 124-125 ° C; [a] δ = -r15.1 ° (chloroform). Example 2 a) In one with a stirrer, The three-necked flask equipped with a reflux condenser and a dropping funnel is made from 18.2 g of magnesium and 46.5 ml (= 106 g) of methyl iodide in 800 ml of absolute ether in a known manner Solution of methylmagnesium iodide prepared, for this purpose a solution of 16.7 g of 6-methyl-5,16-pregnadien-3ß-ol-20-one (IIIa) in 600 ml of toluene added dropwise, the ether as far as possible on the steam bath distilled off and the remaining toluene solution heated on the steam bath overnight. The Grignard solution is diluted with sulfuric acid or ammonium chloride solution decomposed and the aqueous solution extracted several times with ether.

The ether solution is neutralized, dried and evaporated in vacuo. The residue, which in addition to the desired 6,16-dimethyl-5-pregnen-3ß-ol-20-one (IVa) nor the undesired one, created by direct Grignard reaction at the 20-keto group Contains bisnorcholan derivative, is added to 400 g of aluminum oxide (standardized according to Brockmann) chromatographed. Compound IVa can be eluted with benzene, while the undesired Bisnorcholanderivat is only eluted with benzene-chloroform gene.

The benzene eluate is evaporated to dryness and the residue (IVa) recrystallized from ether. Mp. 168 to 169 ° C.

b) Compound IVa is, as described in Example 1, d), in 6a, 16a-dimethyl-4-pregnen-3,20-dione converted.

Claims (2)

PATENT CLAIMS-1. Process for the production of methyl steroids, characterized in that 3,5-cyclo-16-pregnen-6-ol-20-one is used in a manner known per se (1) by treatment with a mild oxidizing agent in 3,5-cyclo-16-pregnen-6,20-dione (II) converts this diketone (1I) by Grignaadation with methylmagnesium bromide or iodide converted into 3,5-cyclo-6,16a-dimethyl-pregnan-6-ol-20-one (III), the latter (III) by the action of a mixture of acetic acid or formic acid and one small amount of a strong acid, preferably sulfuric acid, to form 6,16a-dimethyl-5-pregnen-3ß-ol-20-one-3-acetate (IVb) or -3-formate (IVc) rearranged and optionally this compound (IVb or IVc), if necessary after previous saponification of the 3-formate or 3-acetate group, by treatment with a mild oxidizing agent or by the action of a culture or an enzyme obtained therefrom from Flavobacterium dehydrogenans in 6a, 16a-dimethyl-4-pregnen-3,20-dione (V) converts, or that compound I is converted in a manner known per se by Grignardation with methyl magnesium bromide or iodide in 3,5-cyclo-16a-methyl-pregnan-6-ol-20-one (Ia) transferred, the latter by treatment with a mild oxidizing agent for 3,5-Cyclo-16a-methyl-pregnane-6,20-dione (IIa) is oxidized, this diketone (II a) by Grignardation with methyl magnesium bromide or iodide or by reaction with alkali methyl, preferably lithium methyl, converted into compound III and the latter, as indicated, in compound IVa, IVb or IVc and optionally converts this into compound V, or that in a known manner 6-methyl-5,16-pregnadien-3ß-ol-20-one (IIIa) converted into compound IVa by Grignardation with methyl magnesium bromide or iodide and optionally converting the latter to compound V as indicated. 2. Procedure according to claim 1, characterized in that one for the oxidation of compound IV to form the compound V chromic acid or a mixture of chromic acid in Pyridine or acetone applies or that the reaction under the conditions of a Performs Oppenauer oxidation.