NO124647B - - Google Patents

Description

Process for the production of highly progestatively active 17"-carboxylic acid esters of A<1>'<4->pregnadien-17"-ol-3,20-dione.

17α-carboxylic acid esters of Δα-pregnadien-17α-ol-3,20-dione have not been described so far, although said compound itself in

longer time has been known (see Journ. Am.

Chm.Soc.Bd. 72, pp. 1046 and 4081 [1950] and

English patent document 685,331).

This may be because methods for esterification of the difficult-to-esterify tertiary

17a-hydroxyl group in steroids first became

found relatively recently. Those who first produced the non-esterified compound expected an anti-arthritic effect from it, then

pregnenolone at the relevant time was

attributed to such an effect. It appears

not of the later non-fiction that these

expectations were met.

It was now found that they now for the first time

once prepared 17α-carboxylic acid esters of

A<1>'<4->pregnadien-17a-ol-3,20-dione shows a

strong progestative effect. This is surprising given the known pro-gestational effect of progesterone for it

most are significantly reduced by the introduction of

a further double bond. (Fieser, Natural Products related to Phenanthrene S.

394 [1947].

The production of the new esters takes place: according to usual methods in steroid chemistry. In this way, you can e.g. allow the free Ax'4-pregnadien-17a-ol-3,20-dione to react with the desired low molecular weight carboxylic acids or their reactive derivatives using the now common improved methods in steroid chemistry for the esterification of tertiary hydroxyl groups in 17a- the position. One can also start from 17a-carbon acid esters of such 17a-ols with the general formula where R means a low-molecular acid radical and which instead of the oxo group in the 3-position or in the 20-position or instead of the two double bonds has a group which can be transferred in a known manner to the said oxo groups or double bonds, and transfer the said group by with the help of per se known methods to the latter desired group. This will be explained in more detail in the following execution example: Example 1.

^ J- pregnadiene- lTa- olS^ O- dione- acetate.

18.73 g (50 m mol) of allopregnan-17a-ol-3,20-dione-acetate are dissolved in a mixture of 350 ml of glacial acetic acid and 150 ml of methylene chloride.

The solution is added to 0.65 ml of 32% hydrogen bromide in glacial acetic acid and, at room temperature and while stirring, is added dropwise in

during 25 minutes 15.98 g of bromine (dissolved

in 61 ml of glacial acetic acid). After stirring for a further 20 minutes, more is added

quantities of methylene chloride, then wash with water, bicarbonate solution and again with water. The now neutral methylene chloride solution is dried over sodium sulphate, evaporated to dryness in vacuum under a nitrogen atmosphere and the residue is triturated with pentane. The yield of dibromine crude product is 25.2 g. Melting point 192-193° C (decomposition).

This dibromine product is heated for 25 minutes to boiling with 50 ml of collidine. Immediately for 25 minutes to boil with 50 ml collidine. Immediately after cooling, the mixture is diluted with water, acidified with 2N hydrochloric acid and shaken out with methylene chloride. The methylene chloride solution is washed neutral with water, dried with sodium sulphate, evaporated to dryness and the residue is filtered through 400 g of alumina (Fa. Woelm. acid, containing 1% water) using a mixture of carbon tetrachloride and methylene chloride in a ratio of 1: 1. The obtained crystalline fractions are recrystallized from methanol and yield 12.7 g of the desired A<1>4->pregnadlen compound with melting point 213-216° C. After further purification, the product had a melting point of 222-223° C and a specific rotation of I>]D = + 16.4° (C = 1, CHCl3)

Example 2.

^^- pregnadiene- lTa- olS^ O- dione- capronate.

4.7 g of allopregna-17a-ol-3,20-dione-capronate are dissolved in a mixture of 50 ml of glacial acetic acid and 50 ml of methylene chloride and the solution is added dropwise over the course of 20 minutes, at room temperature and with stirring, 3.48 g of bromine in 12 ml of glacial acetic acid. After a further 20 minutes, the material is worked up as indicated in example 1. The obtained dibromide

crude product is recrystallized from ethanol and has a melting point of 191-192° C.

The subsequent cleavage of hydrogen bromide with the help of collidine takes place as indicated in example 1. After work-up as indicated in example 1, chromatography and recrystallization from 80% methanol, A^-pregnadien-na-ol-S^O- dione capronate with melting point 86-87.5° C.

Claims (1)

Process for the production of highly progressive-acting 17a-carboxylic acid esters of A<1>'<4->pregnadien-17a-ol-3,20-dione, characterized in that the hydroxyl group in the 17-position in A<1 is esterified in a known manner, >4-pregnadien-17a-ol-3,20-dione with low molecular weight carboxylic acids or in 17a-carboxylic acid esters of such pregnadien-17a-ols with the general formula in which R means a low-molecular acid radical, and which instead of either the oxo group in the 3-position or in the 20-position or one of the two double bonds has a group which can be transferred in a known manner to the said oxo groups or double bonds, the said group transfers using methods known per se to the desired oxo group or double bond in the final product.