DE1004177B - Process for the preparation of 5ª ‡ - and preferably 5 ª ‰ -dihydro-3-keto steroids - Google Patents

Description

Process for the preparation of 5α- and preferably 5β-dihydro-3-keto steroids The invention relates to the reduction of the 4-unsaturated 3-keto steroids by catalytic hydrogenation. As is known, they exist through this reduction Compounds produced in two isomeric forms: a form is called normal or cis- or ß-form, while the other is called allo- or trans- or a-form will.

The system of cyclopentanoperhydrophenanthrene, which forms the basic structure of the steroids, contains 6 centers of asymmetry which are identical to the carbon atoms connecting the rings A, B, B / C and C / D. All natural steroids, with the exception of products that act on the heart, are derived from one or the other of the C6 isomers, which, for example, are represented by the formulas of pregnans (I) and allopregnans (II) C2 H5 C HJ 'H H ! H H (I) normal series (A: B = cis; 5ß-form) C2 H5 CH3 H H H (II) Allora series (A: B = trans; 5a form) being represented.

It was agreed that a group would be located above the plain the nucleus extends by a full line and a group that extends below this Plane extends, denoted by a dotted line; the first group will referred to as 5ß-steady and the second as 5a-steady. By appointment assigned the ß-position as a reference system to the methyl group on carbon atom 10. The catalytic hydrogenation of the 5-unsaturated 3-oxysteroids yields almost exclusively saturated derivatives of the 5a series (allo series; A: B = trans).

In the literature, however, examples of the reduction of in 4-position unsaturated 3-ketones to mixtures of ketones, which the Sß- (normal Line; A: B = cis) and 5a (allo series; A: B = trans) series correspond been.

It is also known that alkalis or acids are often the stereochemical Change the course of the reduction and that alkalis contribute to the formation of the 5ß-compounds favor the reduction of the 4-unsaturated 3-ketones of the sapogenin series.

The alkali influence is also in the series of 4-pregnen-3, 20-diones been studied, giving a significant increase in the amount of formed 5ß-Dihydroisom2ren observed when as alkali KOH in methanolic and ethanolic Solution was used, or if the dioxane solution of the substance to be hydrogenated a KOH solution in alcohol is added.

It has now been found, and that forms the subject matter here Invention that the use of triethylamine instead of KOH in the reduction a formation of the isomers of the 5 [beta] series is significantly favored. This result is all the more surprising than with triethylamine, although it is used as an activator of the hydrogenation catalysts is known the ability to reduce in a stereochemical sense like alkalis to change is not known.

To carry out the process according to the invention, the is to be hydrogenated 3-ketosteroid unsaturated in the 4-position dissolved in a solvent; one sets the triethylamine and the catalyst and hydrogenated in the usual way at room temperature and normal Pressure in a hydrogen atmosphere. As a solvent is uses an organic, non-reactive, neutral solvent that is used by Hydrogen is not attacked and does not react with triethylamine, such as ethanol, Ether, ethyl acetate or methylcyclohexane; it is preferably pure p-dioxane used;. Palladium (5%) on charcoal is used as the catalyst; it will be about 0.3 to 0.7 parts by weight of triethylamine and about 1 to 3 parts of 5% Pd containing Charcoal used on 10 parts of the steroid to be reduced. From the circumstances of triethylamine and Pd does not depend on the steric direction, but it does the speed of reaction.

According to the known methods, the desired isomer is obtained from the product deposited. The double bond in a-, ß-position, based on the 3-ketone, is selectively reduced (without other reducible groups possibly in the molecule are present, are attacked). Obtained by the process according to the invention one thereby significantly higher yields of the 5ß-dihydroisomer than those that is carried out with the addition of K O H and in a significantly shorter time than is necessary to carry out the same reaction without the addition of alkali or in the presence of K OH to obtain. For example, there is a reduction in progesterone in a neutral medium Allopregnandione (5a-dihydro compound) and pregnandione (5ß-dihydro compound) im Ratio of about 3: 1; in the presence of K O H of 1: 1 and in the presence of triethylamine from 1: 4.

Furthermore, under the influence of the K 0 H there is the possibility that at Progesterone and its derivatives take place isomerization at carbon atom 17 can; this risk does not exist when using triethylamine.

The advantage of having derivatives of the 5ß-isomers predominantly through To produce reduction of 4-position unsaturated 3-keto steroids consists in that easily reintroduced the 4-position double bond in those compounds which is common to all steroid hormones (testosterone, progesterone, deoxycorticosterone, Cortisone etc.), while in the compounds of the 5a series the introduction of the double bond with very low yields: goes.

This way one can make the corticosteroids more complicated Structure to reduce the 4-position double bond in order to protect it against reagents, which are used for conversions at other points of the steroid. The double bond can can then be reintroduced without significant loss of material as soon as you have the desired chemical structure.

The hydrogenation method of the present invention can easily to reduce z. B. of testosterone, androstenedione, cholestenone, etc. be applied.

The following examples illustrate the process according to the invention. Example 1 2 g of progesterone (4-pregnene-3, 20-dione) are dissolved in 80 cc of dioxane; 1.5 cc of triethylamine and 0.3 g of palladium catalyst (5% Pd on carbon) are added. Hydrogenation is carried out in a hydrogen atmosphere at room temperature and normal pressure. In 15 to 30 minutes, 1 mole of hydrogen is absorbed; the catalyst is filtered off and the solvent is removed and. the triethylamine by vacuum distillation. The residue is taken up again at the boiling point with a little methanol.

The sparingly soluble 5a-dihydro derivative (allopregnan-3, 20-dione) formed is filtered off with heat. It weighs 350 mg and melts at 198 to 200 '. 1.55 g of the β-isomer (pregnane-3, 20-dione), melting point 112 to 118 ', crystallize out from methanol. The two pure substances have a melting point of 200.5 'and 123', respectively. Example 2 10 g of 11α-oxyprogesterone, melting point 160 to 165 ', are dissolved in 280 cc of dioxane at room temperature and normal pressure. 7 cc of triethylamine and 1.4 g of palladium catalyst (5% Pd on carbon) are added and the mixture is hydrogenated.

After 1 mol of hydrogen had been absorbed in 20 minutes, the mixture was filtered the catalyst is removed and the dioxane and the amine are distilled in vacuo. The residue is taken up again with 50 cc of ether. After 24 hours, the allopregnan-3, 20-dione-11 a-ol crystals (5a isomer) filtered, (1.6 g with a m.p. of 180 to 193 '), after recrystallization, mp. 194 to 196'. From the mother liquor can by adding petroleum ether the 5ß-isomer, the pregnan-3, 20-dione-11-a-ol, that melts at 114 to 117 °, win. Since the isolation of this connection with is associated with a significant loss, it is appropriate to use the hydrogenation product, after the alloisomer has been eliminated to oxidize and the pregnane-3, 11, 20-trione to isolate. 7 g of this compound are obtained with a melting point of 145 to 152 '. The pure product melts at 158 to 160 °. Example 3 1 g deoxycorticosterone acetate, Melting point 155 to 157 ', is dissolved in 50 cc of dioxane; 0.7 cc of triethylamine is added and 300 mg of charcoal containing 5% Pd and hydrogenated at room temperature and atmospheric pressure. After 30 minutes, the catalyst is filtered off and the solvent is removed in vacuo eliminated. The residue is crystallized from acetone. 310 mg are obtained 21-acetoxy-allopregnan-3, 20-dione (5a-isomer), m.p. 193 to 195 ', and 550 mg 21-acetoxypregnan-3, 20-dione (5β-isomer), m.p. 146 to 150 '.

The same reduction used by A. Wettstein and F. Hunzicker (Helvetica Chimica Acta, Vol. 23, 1940, p. 764) was made in the absence of triethylamine, gave a yield of 12% of 21-acetoxy-allopregnandione and 32% of 21-acetoxy-pregnandione (Duration 5 hours).

Claims (2)

PATENT CLAIMS: 1. Method of making 5a- and preferably Sβ-Dihydro-3-1, etosteroids by selective catalytic hydrogenation of in 4-position unsaturated 3-keto steroids in the presence of an activator, characterized in that that triethylamine is used as the activator. 2. The method according to claim 1, characterized characterized in that the 4-unsaturated 3-ketosteroid to be hydrogenated dissolved in an inert organic solvent, preferably in pure p-dioxane is that on 10 parts by weight of steroid 0.3 to 0.7 parts by weight of triethylamine and about 1 to 3 parts by weight of 5% Pd-containing charcoal are added and at room temperature and normal pressure is hydrogenated in a hydrogen atmosphere.