DE1768308C3 - Process for the preparation of 17 beta-lactones from 14 beta-hydroxysteroids - Google Patents

Description

(M)

H ₃ CR

25th

It is already known that 3.14 /? - dihydroxy-15-bromo-card-20 (22) -enolide by means of catalytic (noble metal catalysts in a hydrogen atmosphere) hydrogenation in Jie corresponding 3,14j3-dihydroxycard-20 (22) - enolide can convert. It is also known that (Ch. R. E η ge 1 and G. B ach "Steroids" Vol. 3, p. 593 [1964]) 14j3-hydroxy-card-20 (22) -enolide is obtained if 3ß- Hydroxy- 50-carda-14,2O (22) -dienolide (anhydrodigitoxigenin) treated with N-bromoacetamide, the resulting crude IS-bromo-Sß-H / J-dihydroxy-S /? - card-20 (22) -enolide on aluminum oxide chromatography, the resulting 14,150-oxido-card-20 (22) -enolide by treatment with hydrogen chloride in chloroform in the 15 "-Chlor-14j3-hydroxy-card-20 (22) -enolide and then converted into Raney nickel treated in boiling ethanol The yield in this process is 4%; taking into account the starting material obtained back, which can be reacted again, the yield is 6.5%.

The invention relates to a process for the preparation of 17 / J-lactones from 14-hydroxy steroids. These compounds are obtained by converting Carda-14,20 (22) -dienolide or Bufa-14,20 (22) -trienolide with N-bromo-acid amides to the corresponding 15 "-Bromo-14jJ-hydroxy-card -20 (22) enolides or 15a-bromo-140-hydroxy-bufa-2O (22) -dienolides, treated with Raney nickel in an organic solvent at room temperature and then existing 3-oxo groups with metal hydride complexes to give the corresponding , in ring A saturated 3a- or 3j3-hydroxy or the 3j9-hydroxy- <4 ⁴ -derivatives reduced.

The inventive method runs z. B. according to the following scheme:

60

(D

(IH)

OH

where R

HO

/ \
CH ₂ CO

C = CH

/ \
CH CO

Il I

C CH

CH

d. i.e., the cardenolide or the bufadienolide ring means. In the formula scheme, the starting materials (1) can also be used in the 3-position instead of the Oxo group is an OH group esterified with a low molecular weight acyl radical in the α or ^ position being. If the steroid structure is saturated in the 4.5 position, then either the 3-OH group is in the α position and the 5H atom in the ^ position or the 3-OH group is in the ^ -position and the 5H atom in the α-position or in the J3-position; if the steroid structure is 4,5-position unsaturated, a 3-OH group is always in the ^ position.

The acyl radical used is the radical of a mono- or dicarboxylic acid with a maximum of 6 carbon atoms. The acyl radicals of monocarboxylic acids are, for example, formyl, acetyl, propionyl or butyryl radicals into consideration as acyl radicals of dicarboxylic acids, e.g. B. the acyl residues of malonic acid and succinic acid.

The steroid compounds (1) used as starting materials can also be used against N-bromamides inert substituents, such as. B. acyloxy or alkyl groups in 1-, 2-, 4-, 6-, 7-, 11-, 12-, 16-, 17- and / or 19 position.

The Carda-14.20 (22) - used as starting materials

oBde, especially the corresponding zH-3-

rwoderivate, for example according to the procedure

Aes Belgian patent 6 95 311.

J? 1 from starting materials used Bufa-14.20 (22) -

'Nolide can, for example, according to the method according to the German Offenlegungsschrift 16 68 009 can be obtained.

The conversion to the corresponding bromohydrin can be carried out according to the procedure described in Engel and Bach “Steroids” Vol. 3 p. 593., for example by treating with N-bromoacetamide in dioxane in the presence of perchloric acid or by reacting with N bromosulfonamides, preferably aromatic sui -f nsäuren as, Ν-Dibromsulfonamid be in weakly acidic solution, such as RIE in the presence of ₅ acetic acid, in inert solvents such as ethers, "for example, dioxane, tetrahydrofuran or diglyme, carried out, for example, Ν. It is also possible to use other N-bromo acid amides in the presence or absence of perchloric acid and the solvents mentioned, such as, for. B. N-bromosuccinimide and other N-bromocarboxamides. The conversion to the compounds of formula 11 is already known in the case of 5j3-saturated 3 hydroxycard-20 (22) -enolides (cf. Belgian patent 6 97 660), 3-oxo-carda-4,20 (22) -dienolides and S. Hydroxy-Sa-cardenolide and the corresponding bufadienolide have not yet been described.

The crude bromohydrins produced in this way do not require any further purification, but are immediately subjected to treatment with Raney nickel. As far as possible, excess alkali should be removed from the Raney nickel used for reduction by briefly digesting it several times with water (preferably about 3 times with about 10 times the volume of water, based on the amount by weight of the Raney nickel used). By briefly digesting two to three times in a lower alcohol, such as. B. methanol, ethanol or another water-miscible to Raney nickel-indifferent solvent, most of the water is removed. In order to make the catalyst particularly active, it is advisable to pass a stream of hydrogen through the stirred mixture for a while. The hydrogen atmosphere above the Raney nickel suspension can then be replaced by nitrogen. This is particularly advantageous in the case of / 4 ⁴ -3-oxo derivatives, in order to avoid the 4,5 double bond from being saturated here in any case. Part of the organic suspending agent used so far can be reduced by low chlorinated hydrocarbons, such as. B. chloroform or methylene chloride, are replaced. The crude bromohydrin is expediently at room temperature or below in a suitable organic solvent which is miscible with the solvent above the Raney nickel, such as. B. chloroform or methylene chloride, added, if necessary freed of any acid still present by washing with water, then dried with a suitable drying agent such as sodium or magnesium sulfate. This solution, which has been pretreated in this way, is then combined with the Raney nickel suspension, which is expediently vigorously stirred.

The response time, i.e. H. the action of Raney nickel on the bromohydrin is 1 to 20, preferably about 3 hours. The temperature can be between 0 and 30 °, but it is most advantageous a temperature between 18 and about 23 °, i.e.

The amount of Raney nickel to be used must be as large as possible, since smaller amounts cause the undesired 14,15-oxide derivative of the corresponding Cardenolide or bufadienolide derivatives are formed in more or less large quantities 40 times the amount by weight of the steroid used in Raney nickel used.

The method according to the invention is very surprising. As can be seen from the above-mentioned work by Engel and Bach, the hydrogenation of the halogen from derivatives with a cardenolide ring in the 17-position was only possible with the corresponding chlorohydrin and there only in 13% or 25% yield. However, the chlorohydrins first have to be prepared from the corresponding bromohydrins via the relevant oxido derivatives. The hydrogenation of the chlorine atom was achieved here by means of Raney nickel in boiling methanol or acetone, the Raney nickel catalyst having been deactivated beforehand by treatment with acetic acid, apparently in order to suppress the formation of undesired oxide derivatives. In contrast, the yields in the process according to the invention for the cardenolides are about 30 to 70% (compared to 4 to 7.5% of the prior art) based on the Δ ^H derivative used and one can directly dip 15λ-Βγοπι-, 140- Use hydroxy derivatives. This simplified reaction, which proceeds with better yields, could not be foreseen on the basis of the prior art and, moreover, offers great advantages over the known reaction. Halohydrins of bufadienolides have not yet been used for the synthesis of 140-hydroxy-bufadienolides. It is also surprising that in the 3-oxo-4 ^4- cardenolides and -bufadienolides the 4,5 double bond is not attacked under the conditions of the Raney nickel hydrogenation according to the process according to the invention.

The 3-oxo-140-hydroxy-d ⁴ -cardenolides obtained in this way can easily, as already known (Kuno Meyer et al. HeIv. Chim. Acta. Vol. 46, [1963], p. 23), by means of complex metal hydrides to the corresponding cardiac 3-hydroxy-d ⁴ -cardenoliden, such as. B. be reduced to canarigenin.

Lithium aluminum tri-tert-butoxyhydride is preferably used for this purpose in suitable solvents, such as. B. ethers, such as tetrahydrofuran, preferably at Temperatures around 0 °.

In contrast, the corresponding reaction in the case of 3-oxo-bufa-4,20 (22) -trienolides to the corresponding 3j3-hydroxy-bufa-4,20 (22) -trienolides has not yet been described. However, here, too, the reduction with lithium aluminum tri-tert-butoxyhydride succeeds if one works with somewhat longer reaction times and here too with reaction temperatures just below 0 °, since the 3-oxo-4 ⁴ grouping is somewhat slower than the saturated one 3-oxo compound is reduced.

By reducing the corresponding 3-oxo-d ⁴ -bufadienolide compounds of the highly effective scillarenin type are obtained, such as. B. the scillarenin. Canarigenin also shows a strong cardiac activity. ^{The 30-hydroxy-d 4} grouping which has become easily accessible by the process according to the invention is in terms of cardiac effectiveness, the 30-hydroxy-50 grouping, which is more difficult to access (by a partially synthetic route), ζ. B. the digitoxigenin series, to be regarded as equivalent. Also the products of the process of the saturated series

have valuable pharmacological properties, in particular they have positive inotropic and cardiovascular properties Effect. The products of the process can also be used as intermediates for the manufacture of pharmaceuticals be used.

example 1

14j3-Hydroxy-3-oxo-carda-4,20 (22) -dienolide 111
(Anhydroperiplogenin)

2.06 g of 3-oxo-carda-4,14,20 (22) -trienolide are suspended in 21 ml of dioxane (peroxide-free) and initially mixed with 3.4 ml of 0.39 n Perchloric acid is then added. 3 g (1.6 mol equivalents) of N-bromoacetamide are then added in small portions over the course of 30 minutes. Then everything went into solution. The mixture is then stirred for a further hour at 15 to 18 °. Then, after about 3 minutes, the mixture is cooled in an ice bath. The reaction mixture is then stirred into 220 ml of ice-cold water. After stirring for 5 minutes, the precipitated 14 /? -Hydroxy-15 “-bromo derivative is suctioned off, washed with water, then the filter residue is taken up with methylene chloride (about 150 ml, at the end of the operation, a total of 250 ml of solution should be present by washing and rinsing) ). The methylene chloride extract is washed once with water to remove residual mineral acid, dried over sodium sulfate and filtered off from this. In the meantime, the catalyst is prepared as follows. 75 g of water-moist Raney nickel are whirled up three times with 750 ml of water each time for a few seconds and the supernatant water is decanted off after the Raney nickel has settled. The same is repeated, also 3 times with 100 ml of methanol each time. After decanting off the last remaining methanol, 95 g of a methanol-moist Raney nickel paste which takes up a volume of about 55 ml, which corresponds to an amount of about 40 g of dry Raney nickel, are formed. _4C

This suspension is rinsed with 300 ml of methanol into a stirred vessel which is under nitrogen. Thereafter, it is introduced for 2 hours with good stirring I ¹ / hydrogen Then, the stirring is stopped, the reaction vessel flushed with nitrogen, the supernatant siphoned off methanol and finally again stirred for a few seconds after the addition of 75 ml of pure methylene chloride. After the supernatant methylene chloride has been siphoned off, the catalyst is ready and can be used as soon as possible.

For this purpose, the above-described solution of the crude bromohydrin in 250 ml of methylene chloride is added with vigorous stirring poured quickly. The progress of the hydrogenolysis can be monitored by thin-layer chromatography to be tracked. (TLC prefabricated plate, silica gel F254 (Merck); mobile phase: methylene chloride / methanol 19: 1). As can be seen from the TLC, there is no after about 2 to 2 1/2 hours of stirring at room temperature (22 to 23 °) Source material available. The somewhat more polar 14,15-oxido derivative is only weakly indicated in the TLC. &> The most polar and strongest spot with the lowest Rf value is the desired 14j3-hydroxy-cardenolide.

After stirring for 3 hours, the Raney nickel is filtered off with suction and the filter residue is washed thoroughly with methylene chloride which contains 1 to 2% methanol. The ^ ₅ filtrate is washed with water, dried over sodium sulfate and i. V. concentrated to dryness.

The residue is briefly boiled in about 5 to 7 ml of methanol, with 40 mg in cold methanol very poorly soluble 14,15-oxido-3-oxo-carda-4,20 (22) -dienoüd (after cooling) crystallizer .. The filtrate is again concentrated to dryness and then recrystallized from acetone. 1.1 g of 14 /? - Hydroxy-3-oxo-carda-4.20 (22) -dienolide from Mp. 238 to 242 °, [«] = + 96 ± 2 ° (c = 1, chloroform), receive. The mother liquors are evaporated to dryness i.V. and a column of 25 g of aluminum hydroxide (W ο e 1 m), neutral, activity level H, chromatographed. Another 310 mg of the same compound can be obtained with methylene chloride.

3j?, 14/3-dihydroxy-carda-4,20 (22) -dienolide
(Canarigenin)

480 mg of 140-hydroxy-3-oxo-carda-4,2O (22) -dienoid are dissolved hot in 28 ml of isopropanol. After cooling to room temperature, 12 ml of a saturated sodium borohydride solution in isopropanol are added. After standing at room temperature for 15 hours, a mixture of 0.3 ml of glacial acetic acid and 0.5 ml of water is then slowly added dropwise, while cooling with ice and stirring well. The reaction mixture should then show reactions that are as neutral as possible, at most weakly basic. Then the whole thing is concentrated to dryness in a rotary evaporator and triturated with methylene chloride in the cold and the methylene chloride extract, if it still shows a weakly acidic reaction, immediately washed neutral with dilute sodium bicarbonate solution. After drying over sodium sulfate, it is concentrated to dryness in vacuo. After recrystallization from a little acetone / ether and finally again from pure acetone, 235 mg of 3β, 4β-O \ by droxy-carda-4,20 (22) -dienolide of melting point 245 to 257 ° (Kofler melting point) are obtained . The mother liquor is concentrated to dryness and chromatographed on a column of 8.5 g of aluminum oxide (Woelm), activity level H, neutral. Elutions with pure methylene chloride give an additional 70 mg of canarigenin of the same melting point.

Example 2

a) 1 Aβ- hydroxy-3-oxo-bufa-4-20, (22) -trienolide
(14-anhydroscillarenone)

2.14 g 3-oxo-bufa-4,14,20 (22) -tetraenolide (14-anhydroscillarenone) are in 20 ml of dioxane at 15 ° with exclusion of light while stirring with 3.4 ml of 0.39 n-perchloric acid and immediately thereafter within 30 minutes with 1.22 g (1.5 molar equivalents) of N-bromoacetamide in small amounts Portions, staggered. After stirring at 15 ° for 1 hour, the reaction mixture is ice-cold in 300 ml Stir in saturated saline solution.

It was extracted 3 times with 100 ml of methylene chloride each time and the combined organic extracts Washed neutral with a little ice-cold saturated sodium chloride solution, several times if necessary. After drying over sodium sulfate, the pretreated methylene chloride extract is vacuum, immediately concentrated to 150 ml and added to 95 g of methanol-moist, as already described in Example 1, given pretreated Raney nickel. After 5 hours Stirring at 20 °, the catalyst is suctioned off, washed with methylene chloride and, after washing, with Water, dried with sodium sulfate. The residue obtained after concentration in vacuo is eliminated Acetone recrystallized a little methanol. It will be like this

705 mg of 14j3-hydroxy-3-oxo-bufa-4,20 (22) -lrienolide from Melting point 248 to 250 °.

b) 3j3, 14j3-dihydroxy-bufa-4,20 (22) -trienolide

(Scillarenin)

150 mg of scillarenone are dissolved in 15 ml of absolute tetrahydrofuran. After cooling to -5 °, 4.8 ml of a solution of aluminum aluminum tritert-butoxyhydride in absolute tetrahydrofuran (1 ml contains 220 mg of the complex metal hydride) are added dropwise with thorough stirring. After I ¹ / stirring for 2 hours at this temperature is still a further 70 minutes at long - nachgerühn Γ. Then, with sufficient cooling, the internal temperature must not exceed 0 ', a mixture of 10 ml of tetrahydrofuran, 0.3 g of glacial acetic acid and 5 ml of water is carefully added dropwise and with vigorous stirring. After stirring for 45 minutes, during which the reaction mixture slowly rises to room temperature, it is worked up as follows: The reaction mixture is brought to a neutral reaction as far as possible. Then the whole thing is concentrated to dryness in the reaction evaporator and rubbed well in the cold with plenty of methylene chloride. Undissolved inorganic compounds are sucked off sharply and the filter residue is washed several times with methylene chloride and chloroform. The combined organic filtrates, if they still show a weakly acidic reaction, are immediately washed neutral with dilute sodium hydrogen carbonate solution. After drying over sodium sulfate, it is concentrated to dryness in vacuo. After the residue has been degenerated with a little ether, 90 mg of scillarenin with a melting point of 231 ° to 239 ° (Kofler melting point) are obtained.

Example 3

3λ.-Acetoxy-140-hydroxy-5jS-card-2O (22) -enolide

(3-epi-digitoxigenin acetate) ^A °

1.03 g of 3a-acetoxy-5jS-carda-14,20 (22) -dienolide are suspended in 10.5 ml of dioxane (peroxide-free). Then, as described in Example la, 1.7 ml of 0.39 n-perchloric acid and 0.65 g of N-bromoacetamide were added. The mixture is then stirred for 1 hour at 15 to 18 °. Then ice-cold water is stirred into HOmI. After stirring for 5 minutes, the precipitated bromohydrin is filtered off, washed with water, the filter residue is taken up in methylene chloride and the extract is concentrated to dryness after washing with water and drying over sodium sulfate in vacuo at room temperature a suspension of the same, prepared from 37.5 g of moist Raney nickel as described in Example la, in a mixture of a little methanol and methylene chloride. After stirring for 4 hours at 20 °, the catalyst is filtered off with suction and washed with copious amounts of methylene chloride and, after washing with a little water and drying over sodium sulfate, the filtrate is concentrated to dryness in vacuo Inoculation with authentic material brought to crystallization. 420 mg of 3-epidigitoxigenin acetate with a melting point of 210 to 212 ° (Kofler melting bank) are obtained.

Example 4

iß- Formoxy-140-hydroxy-50-card-2O (22) enolide
(Digitoxigenin formate)

A solution of 480 mg of Sß-formoxy-SjS-carda-14,20 (22) -dienolide in 16 ml of dioxane is first mixed with a mixture of 0.344 ml of glacial acetic acid and 2.87 ml of water while stirring. Then 196 mg of freshly recrystallized N, N-dibromobenzenesulfonamide are immediately added to the well-stirred mixture. After stirring for 1 hour while cooling with ice, 30 ml of ice water are added. The deposited precipitate is filtered off, washed with water and taken up in about 20 ml of methylene chloride. After washing this solution with water and drying over sodium sulfate, the solution, which has been made up to a total volume of 24 ml, is stirred into a suspension of a nickel catalyst obtained from 19.5 g of moist Raney nickel, which has been worked up as in the previous examples. After 2 ^! / 2 hours of stirring at 26 ° is worked up as usual. The methylene chloride filtrates and extracts separated from the catalyst are concentrated to dryness in vacuo after washing with water and drying. For further purification, the crude digitoxigenin formate obtained is dissolved in a little benzene and chromatographed on a column consisting of 3.75 g aluminum oxide (Woelm), neutral, activity level II.

After recrystallization from a little ether / acetone, elution with benzene gives 225 mg of digitoxigenin formate from melting point 204 to 206 (Kofler melting bank).

Example 5

3 (J-acetoxy-14 ^ -hydroxy-5 "-card-20 (22) -enolide
(Uzarigenin acetate)

To a solution of 670 mg of 3 ^ -acetoxy-SÄ-carda-14.20 (22) -dienolide in a mixture of 23 ml of dioxane, 0.44 ml of glacial acetic acid and 3.7 ml of water, at a reaction temperature of about 5 °, 260 mg N, N-dibromobenzenesulfonic acid amide added in portions and with stirring. The resulting reaction solution was then left to stand for 3 hours at 20 °. is stirred into 100 ml of semi-saturated sodium chloride solution. The precipitated crude 30-acetoxy-15a bromo-140-hydroxy-5a-card-2O (22) -enolide is filtered off, washed with a little water, taken up in 25 ml of methylene chloride, this solution is washed again with water, dried over sodium sulfate and rapidly added dropwise with vigorous stirring to a suspension of this catalyst, prepared as already described in the preceding examples, from 27 g of water-moist Raney nickel in a little methanol / methylene chloride. After a reaction time of 3 hours, the catalyst is suctioned off with methylene chloride and the combined filtrates are washed Washed again with water and, after drying, evaporated to dryness in vacuo. The residue is caused to crystallize by trituration with a little ether, to which a few drops of acetone are added up to 218 ° C.

609 684/53

Claims (1)

68 Claim: Process for the preparation of 17β-lactones from 14 /? - hydroxysteroids, characterized in that Carda-14,20 (22) -dienolide or Bufa-14,20,22-trienolide in a known manner with N-bromine acid amides to the corresponding 15a-bromo-140-hydroxy-card-2O (22) -enoids or 15 <x-bromo-14 /? - hydroxybufa-20,22-dienolides, these with Raney nickel in one Treated organic solvent at room temperature and then reducing existing 3-oxo groups in a manner known per se with metal hydride complexes to the corresponding 3a- or 30-hydroxy- or 3jS-hydroxy-4 ⁴ derivatives saturated in ring A H ₃ C