DE1144271B - Process for the preparation of 17ª ‰ acetyl steroids - Google Patents

Description

Process for the preparation of 17β-acetyl steroids The invention relates to a process for the conversion of 17x-acetyl-17p-acyloxysteroids to the corresponding ones Compounds with a ß-acetyl or pregnane side chain.

The present method thus constitutes a valuable method for the production of, for example, progesterone or 19-nor-progesterone from appropriate 17a-ethynyltestosterone compounds or from 17x-ethynylestradiol.

The inventive method is characterized in that one a corresponding 17: x-acetyl-17ß-acyloxysteroid with an alkali or alkaline earth metal in liquid ammonia and then with a low molecular weight aliphatic Converts alcohol.

The new method according to the invention is illustrated by the following equation, in which only the ring D of the steroid structure is shown: In the above equation, R stands for an acyl group of a hydrocarbon carboxylic acid with up to 12 carbon atoms, ie for customary known ester groups such as the acetate, benzoate or cyclopentylpropionate group.

The starting materials for the present process are after a known processes from the corresponding 17ß-hydroxy, 17a-ethynyl compounds produced, according to which for the purpose of forming the 17a-dihaloacetyl group from the 17a-ethinyl group a treatment with positive halogen and then an elimination of halogen carried out becomes (Fieser and Fieser, Natural Products related to Phenanthrene, Third Edition, P. 438).

In carrying out the process according to the invention, the starting product, if this contained a 3-position keto group, converted into a 3-enol ether compound. The starting compounds were then treated with an alkali metal for 1/2 to 2 hours or alkaline earth metal treated in liquid ammonia, whereupon a low molecular weight aliphatic alcohol such as methanol was added. After evaporation and cleaning the product obtained consisted of the corresponding one in the case of an alkaline earth metal 17β-acetyl compound. If an alkali metal was used, the one in the 20-position was also used existing keto group is reduced to a 20-hydroxyl group, which is, however, replaced by the usual Agents such as chromic acid are easily oxidized back to the 20-keto group could. Another benefit of using an alkali metal in ammonia occurs when the starting compound has an aromatic ring A, as in the acetate of 3-methyl ether of 17oc-acetyl estradiol. In this case, the aromatic ring also becomes reduced so that by hydrolysis of the ether group and oxidation 19-nor-progesterone is obtained.

The following examples explain the process according to the invention. Example 1 A solution of 2 g of 17a-acetylestradiol diacetate in 20 cc of anhydrous Dioxane was added to a solution of 1 g calcium in 300 cc liquid ammonia and the mixture was stirred for 1 hour. 5 cc of methanol were then quickly added, and the mixture was stirred for an additional half hour and with 5 g of ammonium chloride offset. The ammonia was evaporated, the residue was diluted with water and the Solid filtered off, washed with water, dried and extracted from ethyl acetate recrystallized. In this way, 17AA-acetyl-1,3,5-oestratrien-3-ol with a melting point of 244 to 247 ° C. was obtained. Repeated recrystallizations from the same solvent resulted in a. product obtained from m.p. 247 to 249 ° C, [ajD + 164 ° (chloroform), which in a mixture with pure An authentic sample of this compound did not result in a lowering of the melting point; the Infrared spectra were identical.

Example 2 A solution of 2 g of acetate of 17a-acetylestradiol-3-methyl ether in 20 cc of anhydrous dioxane was added to a solution of 1 g of lithium in 500 cc of liquid ammonia and the mixture was stirred for 1 hour. Then 50 cc of methanol and, after 15 minutes, a further 4 g of lithium were added with continued stirring. The ammonia was evaporated and, after the addition of water, the resulting product was filtered off. Without further purification, the product, which had been refluxed for 1 hour with 30 cem aqueous hydrochloric acid and 50 cc methanol, was cooled and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the ethyl acetate evaporated. The oily residue was dissolved in 50 cc of acetone and treated at room temperature for 1 hour with an excess of 8N chromic acid, which was prepared in the usual way by dissolving chromium trioxide in a mixture of concentrated sulfuric acid and water. After dilution with water, the crystallized precipitate was filtered off, washed with water, dried and dissolved in benzene. The solution was filtered through a short column of neutral alumina (aluminum oxide), the filtrate was evaporated to dryness and the residue was crystallized from a mixture of acetone and hexane, whereby 19-nor-progesterone with a melting point of 141 to 144 ° C was obtained, which showed no degradation when mixed with an authentic sample of 19-nor-progesterone; [a] D + 154.5 ° (chloroform), A.ax 240% t, log F 4.25. The infrared spectrum was identical to that of an authentic sample of 19-nor-progesterone. Example 3 A solution of 1 g of 3-ethoxy-17β-alcoxy-19-nor-.d 3.6-pregnadien-20-one in 25 cc of anhydrous dioxane was added to a solution of 0.5 g of calcium in 250 cc of liquid ammonia and the mixture was stirred for 30 minutes. 4 g of ammonium chloride were then added, the ammonia was evaporated, the residue was admixed with water and the solid was filtered off. The latter was in a mixture. from 5 ccm of concentrated hydrochloric acid and 25 ccm of water heated under reflux, cooled, diluted with water and the product extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The oily residue was purified by filtration through a short column of neutral alumina, whereupon the solvent was evaporated and the residue was crystallized from a mixture of acetone and hexane. In this way, 19-nor-progesterone with a melting point of 140 ° to 142 ° C. was obtained which, when mixed with an authentic sample of the compound, gave no reduction.

Example 4 2 g of the 3,17-diacetate of isoallopregnan-3β, 17β-diol-20-one in 20 cc of anhydrous tetrahydrofuran were added to a solution of 1 g of lithium in 500 cc of liquid ammonia were added and the mixture was stirred for 1 hour. Thereon 4 g of ammonium chloride were added, the ammonia was evaporated, the residue carefully mixed with water and the solid filtered off. Purification of the residue crystallization from a mixture of acetone and hexane gave allopregnan-3β-ol-20-one.

Example 5 Using the procedure described in Example 4, but with the replacement of tetrahydrofuran by diethyl ether and lithium by Sodium, the same allopregnan-3β-ol-20-one was obtained.

Example 6 Using the procedure described in Example 14, but when the lithium was replaced by potassium, the same allopregnan-3ß-ol-20-ou became obtained in practically the same yield.

Example 7 Was obtained according to Example 3 from the ethylenol ether of 17ß-acetoxy-iso-progesterone assumed progesterone was obtained.

Claims (2)

PATENT CLAIMS: 1. Process for the production of 17ß-acetyl steroids, characterized in that a corresponding 17a-acetyl-17p-acyloxysteroid, whose 3-position keto group, if present, has been temporarily protected, with an alkali or alkaline earth metal in liquid ammonia and then with a low molecular weight aliphatic alcohol and, if the reaction in In the presence of an alkali metal, the obtained 20-hydroxy compound oxidized in a manner known per se with chromic acid. 2. The method of claim 1 and 2, characterized in that calcium is used as the alkaline earth metal.