DE1297604B - Process for the preparation of delta 4, 16-pregnadien-20-ol-3-one - Google Patents

Description

The present invention relates to a particularly advantageous process for the preparation of zl ^{4 '16} -pregnadien-20-ol-3-one, characterized in that the oxidizing ring is converted into 17,20-oxido-zl ⁴ -pregnen-3-one with hydroiodic acid cleaves and the Πβ-iodine / ^{I 4} -17-iso-pregnen-20-ol-3-one obtained with a lower alcohol, in particular methanol, optionally in the presence of basic reagents, in particular of alkali or alkaline earth metal hydroxides or of potassium, Sodium or ammonium acetate.

The process according to the invention is thus characterized by the following reaction scheme:

The 17,20-oxido-zJ * -pregnen-3-one (I) used according to the invention as the starting compound is known per se. On the basis of the investigations by L. Ruzicka (HeIv. 25, 1680/1942) it is also known that this compound I is extremely sensitive to acidic reagents. For example, I rearranges in acetic acid solution to Π fr- methyl -18- nor- <d ⁴ - ^{13 (14)} -17a-pregnadien-20-ol-3-one. On the basis of additional own experiments it was found that the described rearrangement also takes place with other acids such as p-toluenesulfonic acid, sulfuric acid and dimethyl sulfoxide. It was therefore not foreseeable that 17,20-Oxidozd ⁴ -pregnen-3-one would result in splitting of the 17,20-Oxidoringes with hydriodic acid into the previously unknown Π β - iodine ^{- I 4} -17 - iso - 20 - Can transfer ol-3-one (II).

The further processing of II to d ^4ll6 -pregnadien-20-ol-3-one is preferably carried out in a lower alcohol, ζ. Β. Methanol. Simply by leaving it to stand at room temperature, the 17-iodine atom is eliminated as HJ with the formation of the corresponding d ¹⁶ compound (III). The reaction can be carried out by increasing the reaction temperature and / or by adding such reagents which are known to the person skilled in the art to be suitable for forming epoxy rings from halohydrins, such as, for. B. alkali or alkaline earth metal hydroxides or their salts or potassium acetate, ammonium acetate or aluminum oxide, are accelerated.

The implementation II -> III according to the reaction scheme indicated above was also surprising, after it is known by N. L. Wendler (Tetrahedron 3,144 [1958]) that 17-bromo-20-olsteroide by treatment with alkali into 17,20-oxidosteroids be transferred.

In the process according to the invention, as set out above, the individual stages are also inventive, which is why element protection is claimed for stages I - * II and II -> III.

The 17,20 - oxido - Δ ⁴ - pregnen-3 - one (I) used as starting material for the process according to the invention was previously prepared from the corresponding Α ^{ίΊ (20)} - compound by methods known per se, but the yield achieved was unsatisfactory is because the conjugated ^ double bond also present, especially when using an excess of epoxidation reagent, e.g. B. monoperphthalic acid or benzoic acid, is also epoxidized to a greater or lesser extent. After it was recently proposed to carry out the desired 17 (20) -epoxidation particularly advantageously by means of m-chloroperbenzoic acid, because this reagent epoxidizes the zl ^{17 (20)} double bond selectively in practically quantitative yield, the present process according to the invention is of particular technical interest because it thus becomes possible, e.g. B. ergosterol degradation products, such as ./J ⁴ -3-keto-bisnorcholenic acid, via the corresponding 20 - halogen, 17.20 - en - compounds, the 17,20-epoxide I and using the method according to the invention in a simple manner in the ^{zJ 4> 16} -pregnadien-20-ol-3-one which can be prepared according to the invention. The latter ultimately serves as the starting product for the preparation of, for example, 16-dehydroprogesterone, which in turn is known to be an important starting product for the partial synthesis of active hormone substances, e.g. B. 17a-Hyrlroxy-progesteron and its esters.

For the production of the starting material, protection is not given in the context of the present invention desired.

example 1

17,20-oxido, d ⁴ -pregnen-3-one is dissolved in 500 ml of tetrahydrofuran at 0 ⁰ C under nitrogen atmosphere and stirring. 14.3 g of constant-boiling hydriodic acid are added dropwise over the course of 30 minutes and the solution is stirred ^{at 0 ° C. for a further 30 minutes.} The reaction solution is then poured into 1500 ml of ice water. The substance precipitated and separated off consists of a mixture of 17 / ^{I-iodine-I 4} -17-iso-pregnen-20-ol-3-one and zl ^{4> 16} -pregnadien-20-ol-3-one. The substance mixture, washed with water and dried, is dissolved in 250 ml of methanol, mixed with 20 g of potassium acetate and stirred overnight at room temperature. The reaction solution is introduced into 2500 ml of ice water and the precipitate formed is filtered off, washed and dried. This gives 18.6 g of ^{4> 16} -pregnadien-20-ol-3-one which, after recrystallization from acetone, melts at 186 to 188.degree.

Example 2

14.3 g of 17y3-iodine / d ⁴ -17-iso-pregnen-20-ol-3-one in a mixture with J ⁴⁴⁶ -pregnadien-20-ol-3-one, prepared as described in Example 1 in 200 ml

Dissolved butane oil and heated for 1 hour. The reaction solution is then concentrated in vacuo. 11.8 g of zl ^446- Pregnadien-20-ol-3-one are obtained, which, after recrystallization from acetone, melts at 186 to 188 ° C.

Claims (2)

Patent claims: 1. A process for the preparation of zl ^{4> 16} -pregnadien-20-ol-3-one, characterized in that the 17,20-oxidizing ring is cleaved with hydroiodic acid in ^{17,20-OxidozJ 4 -pregnen-3-one and} the 17 /? - iodine / l ⁴ -17-iso-pregnen-20-ol-3-one obtained is reacted with a lower alcohol, optionally in the presence of basic reagents. 2. Process for the production of 17 / I-iodine Δ ⁴ - 17 - iso - pregnen - 20 - oil - 3 - one, characterized in that the 17.20-oxido ring in 17.20-oxido-zl ⁴ - pregnen-3-one splits with hydriodic acid. 3 _p . Process for the preparation of zl ^{4> 16} -pregnadien-20-ol-3-one, characterized in that Πβ-ίοά-Δ * - 17-iso-pregnen-20-ol-3-one by treatment with a lower alcohol , in particular methanol, optionally in the presence of basic reagents, in particular of alkali or alkaline earth metal hydroxides or their salts or of potassium, sodium or ammonium acetate or aluminum oxide.