DEC0009874MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration date: August 28, 1954 Bekanmtgiemacht on June 21, 1956

GERMAN PATENT OFFICE

Therapeutically effective, unsaturated in ii (i2) position Pregnans, e.g. B. the 4, ii-Pregnadien-

3, 20-dione (11 (i2) -dehydroprogesterone) and the

4, ii-Pregnadien-21-01-3, 20-dione (11 (i2) -Debydrodesoxycorticosterone), comes because of its stronger effect in comparison to the corresponding compounds saturated in the 11 (12) position Interest in: Since, however, the previously known procedures for the introduction of a 1.1 (12) - permanent. Double bond Delivering very poor yields in Pregnane, it has not been possible to date to produce Pregnane with a Introduce double bond in 11 (12) position into therapy.

It has now been found that unsaturated 11 (.12) position pregnanes can be obtained in a simple manner and good yield (° / ₀ to about 8o), when starting from pregnanes which an oxy group in one of the positions 11 or 12 and in the other position have a halogen atom, and these are treated with a metal of group II of the Periodic Table of the Elements in the presence of an acid or an alcohol.

According to this method, it is now possible to produce therapeutically effective substances which are unsaturated in the 11 (i2) position Pregnane or intermediate to: gain their representation.

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In the halohydrins used as starting materials The groupings necessary for a therapeutic effect can already be used in the pregnancy series to be available; However, these can also be post-. be introduced later. So one can get from connections go out that have double bonds in particular in the 4 (5) or 5 (6) position or Jauch further substituents, for example free or functionally modified oxy or oxo groups, are preferred in the 3- and 20- and optionally in the 17- and / or or 21-position. A functionally modified one Oxy group is e.g. B. one with an aliphatic, aromatic or heterocyclic carboxylic acid, for example Acetic acid, propionic acid, benzoic acid or furancarboric acid, esterified or an etherified Oxy group, e.g. B. the tetrahydropyranyloxy, benzyloxy or triphenylmethoxy group. The functionally modified oxo group is advantageously one ketalized oxo group derived in particular from

a dihydric alcohol, such as the ethylenedioxy group, or an enolized oxo group. The transformation the ineffective products of the process in therapeutically effective compounds can after an known methods are carried out. The above-mentioned starting materials, those of the Pregnan range can be of any steric configuration. They are known or can be produced by known methods. In particular, they can be according to the method of Prepare patent application C 8460 IVb / 12 ο.

For the procedural treatment with metals of the II. Subgroup of the periodic table of Elements is particularly suitable zinc. It is preferable to work in the presence of a weak acid,

z. B. an aliphatic carboxylic acid such as acetic acid, or an aliphatic alcohol such as methanol, Ethanol or propanol.

The invention is illustrated by the following examples.

example 1

0.415 g iia-Brompregnan-SSA, 12, 20-triol ³ are 95 dissolved in 50 cm ° / _o sodium ethanol, ⁸ zinc dust (etched with 2.5 cm with ice-cold 2 η-sulfuric acid, washed thoroughly with boiled water and the water then by 95 ° _o sodium / ethanol displaced) was added, the reaction mixture is boiled then 4 hours under vigorous stirring at reflux. The zinc is then filtered off while still warm while rinsing with ethanol and benzene, and the ritrate is evaporated in vacuo. The residue is dissolved in ether - benzene (2: 1), the solution washed successively with 0.2 η-acetic acid, water, 2 ° / _o sodium bicarbonate solution and water, and evaporate the dried with sodium sulfate solution. This gives 0.324 g of crude ii-Pregnen-30 !, 20-diol, which can be further converted as follows:

0.324 g of the diol obtained above is dissolved in 75 cm ^{3 of} anhydrous toluene and 10 cm ^{3 of} cyclohexanone and 25 cm ^{3 of} solvent are distilled off for dehydration. After adding 0.408 g of aluminum isopropoxide, the mixture is refluxed for 1 hour. 25 cm ^{3 of} molar Seignette salt solution are then added and treated with steam. After ¹ 'cooling, the reaction product is taken up in ether _: benzene (2: 1), washed with molar Seignette salt solution and water, dried with sodium sulfate and the solution is evaporated: the residue is added to 12 g of aluminum oxide after passage method chromatographed. The detached by paper uniform with hexane-benzene fractions give upon recrystallization from ether 0.263 g of pure ii-Tregnen-3, 20-dione, mp = 132 to 134 ^0; [α] «? = + 76 ° ± 4 ° (c = 1.130 in chloroform).

Example 2

A solution of 0.411 g of i2a-bromopregnane-ii / 3-0I-3, 20-dione in; 40 cm ^{3 of} glacial acetic acid is refluxed with 2.5 g of zinc dust for ¹ ^ hour. Then is filtered from the zinc with thorough rinsing with o, 5 _^0/0 sodium ethanol and ether, and the filtrate is evaporated in vacuo. The residue is taken up in ether-benzene (2: 1), the solution. successively with 0.2 η-acetic acid, water, washed 2 ° / _o sodium bicarbonate solution and water; • After drying with sodium sulfate, the solvents are distilled off. Is obtained by recrystallization from ether-petroleum ether 0.263 g n-pregnene-3 from the crude product, 20-dione, mp = 132 to 134 ^0; Μ ο = + 78 ° ± 4 ° (c = 0.983 in chloroform).

If, according to the above example, 50 cm ^{3 of} propionic acid is used instead of glacial acetic acid and after 15 minutes of boiling it is worked up in the manner described, 0.280 g of n-pregnene-3, 20-dione with a melting point of 132 to 134 ^{0 is obtained} .

Example 3

A solution of 0.456 g i2a-iodo-4-pregneniijÖ-ol-3, 20-dione in 120 cm ³ 95 ° / _o sodium ethanol with 5 cm ³ of zinc dust (activated in the direction indicated in Example 1) for 24 hours at room temperature touched. One then filtered from the zinc pad rinsing with 95 ° / _o sodium ethanol and benzene, and the filtrate is evaporated in a vacuum! The residue is worked up as described in Example 2 by extraction. For purification, the crude product is chromatographed on 20 g of aluminum oxide using the continuous flow method. The eluates obtained with hexane-benzene (3: 1) and (1: 1), which turn yellow with tetranitromethane, give 0.285 g of pure 4, ii-pregnadiene-3,20-dione with a melting point of 178 when recrystallized from ether-petroleum ether up to 180 °; [ct] | ³ = + 176 ° ± 4 ° (c = 1.049 ^m chloroform).

The starting materials used in the above examples can advantageously be according to the in the patent application C 8460 IVc / 12 ο described Establish processes in connection with reactions known per se.

Example 4

A mixture of 0.426 g of iia-bromo-4-pregnen-12, 2i-diol-3, 20-dione, 3 cm ^{3 of} zinc dust (etched with ice-cold 2 η-sulfuric acid, washed thoroughly with boiled water and the water then displaced by propanol ) and 85 cm ^{3 of} propanol is heated to the boiling point for ^{2 1} Z _{8 hours with vigorous stirring}

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Heated water bath. After cooling, it is filtered off and the filter residue is washed with methylene chloride. The filtrate is diluted with water, neutralized with sodium bicarbonate and then extracted with methylene chloride. The combined extracts are washed with water, dried with sodium sulfate and evaporated. The residue obtained in this way is dissolved in 4.4 cm ^{3 of} pyridine and 3.3 cm ^{3 of} acetic anhydride and left to stand for 20 hours at room temperature. The reaction mixture is then evaporated in vacuo, the residue taken up in methylene chloride, the solution washed thoroughly successively with water, 0.5N sodium bicarbonate solution and water, dried with sodium sulfate and evaporated. 0.212 g of 4, ii-pregnadien-21-ol-3,2O-dione-2i-acetate is obtained from the crude product by recrystallization from acetone-isopropyl ether in colorless prisms with a melting point of 179 to 18 °. [a] |? = + 175 ° ± 4 ° (c = 0.612 in chloroform).

Claims (4)

PATENT CLAIMS: i. Process for the production of in n (i2) position unsaturated pregnans, characterized in that one pregnans in one of the Positions 11 or 12 contain an oxy group and a halogen atom in the other position, with a metal of the II. subgroup of the Periodic Table of the Elements in the presence of a Treated with acid or an alcohol. 2. The method according to claim 1, characterized in that that iia-halogen-12-oxy-, iia-halogen-12/3-oxy-, I2a-halogen-11-oxy- or i2a-halogen-n /? - oxy-pregnane as well as those pregnans which have an oxy group in one of the positions 11 or 12 and in the other Position have a halogen atom and those in 3- and 20- and optionally in 17- and or or 2i position a free or functionally modified one Contain an oxy or oxo group or a double bond in the 4 (5) or 5 (6) position, in particular iia-bromo-12-oxy- or I2a-iodine-11 / S-oxy-pregnane, used. 3. The method according to claim 1 and 2, characterized characterized in that with zinc and with an aliphatic carboxylic acid, especially acetic acid, is working. 4. The method according to claim 1 and 2, characterized in that one is with activated zinc and an aliphatic alcohol, especially ethanol, works. 609 546/498 6. 56