DE1246728B - Process for the production of 11-oxygenated 17alpha-hydroxy-6, 16alpha-dimethyl-4, 6-pregnadiene or. -1, 4, 6-pregnatrien-3, 20-dione - Google Patents

Description

XJNDES REPUBLIC OF GERMANY

EUCHES

PATENT OFFICE

EDITORIAL

(l

Int. Cl .:

German class:

Number:
File number:
Filing: Auslegetag:

C 07 J \ lbvi /

C07f

M 50554 IV b / 12 ο
October 11, 1961
August 10, 1967

The invention relates to a method of manufacture of new 11-oxygenated 17 "-hydroxy-6,16a-dimethyl-4,6-pregnadiene- or -1,4,6-pregnatriene-3,20-dione of the general formula

CH ₂ R

C = O

CH ₃

in which R is a hydroxyl, acyloxy or phosphoric acid ester group, Ri is a hydroxyl or keto group, X represents a hydrogen or halogen atom and wherein the bond between the carbon atoms 1 and 2 can be saturated or unsaturated.

The new, an 11-position oxygen substituent comprising 17a, 21-dihydroxy-6,16u-dimethyl - 4,6 - pregnadiene - 3,20 - dione and 17 «, 21 - dihydroxy-6,16a-dimethyl-1 Ao-pregnatrien ^^ O-dione, their 9-halogen derivatives and 21-esters have a pronounced anti-inflammatory, anti-rheumatic and anti-arthritic properties and glucocorticoid activity and are particularly valuable in treating arthritis and related diseases as they are to be administered in extremely small doses to develop their cortisone-like effect need, thereby reducing undesirable side effects. In particular, they have Compounds in contrast to cortisone and similar compounds have an extremely strong sodium secretion Effect without a significant potassium excreting effect, so that they also as effective diuretic agents can be used.

The process according to the invention consists in dehydrating a corresponding 21-acyloxy-4-pregnene in a manner known per se with the aid of a substituted chmone, in particular chloranil, in the 6 (7) position, the 21-acyloxy-4,6 obtained in this way -pregnadiene optionally dehydrated with the aid of selenium dioxide in the 1 (2) position, the obtained I ⁴ ■ «- or .

Process for the preparation of 11-oxygenated 17 <% - hydroxy-6,16a-dimethyl-4,6-pregnadiene-
and -1,4,6-pregnatriene-3,20-dione, respectively

Applicant:

Merck & Co., Inc. Rahway, N. J. (V. St. A.)

Representative:

Dr.-lng. W. Abitz and Dr. D. Morf,

Patent Attorneys, Munich 27, Pienzenauer Str. 28

Named as inventor:

Glen Edward Arth, Cranford, N. J .;

John Fried, Plainfield, N.J .;

Lewis Hastings Sarett, Princeton, N.J. (V: St. A.)

Claimed priority:

V. St. v. America October 19, 1960 (63 497)

The dehydrogenation according to the invention with a substituted quinone, in particular chloranil (tetrachloroquinone), takes place using a 21-acylate of the starting material in order to avoid extensive degradation of the dihydroxyacetone side chain. The reaction is advantageously carried out by the reactants in a solvent, such as a lower fatty acid ester, alcohols, organic acids or mixtures of such esters and acids, act on each other. Typical examples of such solvents are ethyl acetate,

Propyl acetate, ethyl alcohol, tert-butyl alcohol, acetic acid or mixtures of ethyl acetate and acetic acid. According to a particular embodiment of the invention Method is the 21-acetate of 11 / i, 17n, 21-trihydroxy-6ü, 16u-dimethyl-4-pregncn-

3,20-dione suspended in ethyl acetate and acetic acid and mixed with about twice its weight of chloranil. The suspension is taking Nitrogen heated under the reflux condenser for about 15 to 20 hours, the 21-acetate of 11 / i, 17a.21-trihydroxy-6,16a-dimethyl-4,6-pregnadiene-3,20-dione forms. This product is conveniently obtained by extraction with an organic solvent and

709 620/576

3 4

subsequent chromatography on activated aluminum, the corresponding 11-oxygenated 21-iodine-17a-hy?

minium oxide obtained. droxy-o.loa-dimethyl- ^ o-pregnadiene- or -1,4,6-

Similarly, the 21-acetate becomes entpregnatriene-3,20-dione.

speaking 11-keto compound, namely 17a, 21-di- This 21-iodine steroid is with a phosphoryhydroxy-6α, 16α-dimethyl-4-pregnen-3, ll, 20-trion-5 lating agent to the corresponding 21-phosphorus-21- acetate, converted into 17a, 21-dihydroxy-6,16a-dimethyl acid ester. As a phosphorylating agent 4,6-pregnadiene-3, ll, 20-trione-21-acetate converted. you can use an inorganic phosphate, ζ B. Mono-The dehydrogenation with selenium dioxide is advantageous silver phosphate, or an organic phosphorus by using the 11-oxygenated acid ester obtained, z. B. a bis-aralkyl orthophosphate, such as 17a, 21-dihydroxy-6,16a-dimethyl-4,6-pregnadiene _l0 dibenzyl orthophosphate, use. If 3,20-dione-21-acylate is used in the presence of an organic phosphoric acid ester, the reaction is advantageously carried out with an alcoholic solvent, such as dioxane, by adding a salt of the solvent, such as tert-butanol, with selenium dioxide, orthophosphoric acid-bis -aralkylesters in an organic and the mixture heated to a higher niche solvent, such as benzene, toluene, xylene temperature. In this reaction, it has _{proven to be advantageous, 5} or dioxane, together with the 21-iodo steroid that the reaction mixture brings about. Small amounts, preferably 1 or 2 drops, of a salt whose cation contains insoluble mercury are used as the salt of the phosphoric ester in order to suppress the formation of undesired iodides in the organic by-products used in the reaction. If tert-butanol forms a niche solvent, such as silver dibenzyl is used as the solvent, the _{um- 2} o orthophosphate, sodium dibenzyl orthophosphate, casetting is preferably carried out at the boiling point of the solution lium dibenzyl orthophosphate, barium dibenzyl orthophosphate, and it is usually about phosphate or calcium dibenzyl orthophosphate. The 15 hours has ended. The metallic selenium reaction is conveniently carried out at the reflux temperature of the solvent, usually filtered off from the reaction mixture, and the filtered solution in vacuo to dryness is usually complete in about 4 to 26 hours. evaporated, the desired 11-Oxyge- working with monosilver phosphate as phosphate na ^ l-dihydroxy-o ^ oa-dimethyl-l ^ .o-prc- phorylierungsmittel, the reaction is durchgnatrien-3,20-dione-21 acylate, z. B. ΙΙβ, Πα, Ιί- led by the 21-iodine steroid with a trihydroxy - 6,16a - dimethyl - 1,4,6 - pregnatrien- mixture of silver phosphate and phosphoric acid to -3,20 - dione - 21 - acetate or 17u, 21-dihydroxy- 30 brings together, which preferably contains about 2 moles of 6,16a-dimethyl-1,4,6-pregnatrien-3,11,20-trione-phosphoric acid per mole of yellow silver phosphate (tri-21-acetate. Das The crude product obtained in this way contains silver phosphate). A small additional amount is expedient by means of paper strip chromatography. An excess of phosphoric acid is advantageous; one phie or by chromatography on silica gel can, however, also be purified with an aluminum oxide which is less than that of an activated or activated aluminum oxide. After 35 given amount of phosphoric acid work. Konder separation of the dehydrogenation product from centered phosphoric acid, e.g. B. 85 or 100% of the unreacted starting material can be the pro-phosphoric acid, is preferred. This mixture of ductile, optionally by recrystallization from silver phosphate and phosphoric acid, behaves in the case of a solvent such as ethyl acetate or one of the reaction as well as monosilver phosphate mixture of ethyl acetate and petroleum ether, further 40 (AgH ₂ POi). The silver phosphate, the phosphoric acid are purified. and the 21-iodine steroid can be mixed with each other at the same time at the beginning of the conversion. Mix the phosphoric acid together beforehand. In the practice of genetically modified 17a, 21-dihydro.xy-6,16'-dirnethyl-4,6-pre- ₄₅ , it is preferable to mix finely divided silver nadiene or 1,4,6-pregnatriene-3,20-dione. phosphate so intimately with the phosphoric acid that an The reaction is expediently carried out, results in a poor dispersion. The reaction between the reaction components in solution in the 21-iodo steroid and the monosilver phosphate of a tertiary amine such as pyridine, preferably at, is advantageously carried out in an inert organic solvent at a temperature of about 0 to 5 ° C. Acetonitrile has been allowed to act. Under these conditions the particularly advantageous solvent has proven; reaction usually takes about an hour, but various other solutions can also be used. The reaction mixture is solvent with water, such as diethyl ether, 1,4-dioxane, tetra-thin and the precipitate is isolated and dried. hydrofuran, acetone or dimethyl sulfone. This gives the corresponding 11-oxygenated reaction temperature and reaction time are not critical to 17a, 21-dihydroxy-6,16a-dimethyl-4,6-pregnadiene; however, the reaction is increased by or 1,4,6-pregnatriene-3,20-dione-21-methanesulfonate. Accelerated temperature. The 21-methanesulfonate obtained is advantageously carried out with a settlement at the reflux temperature. Alkali iodide, such as sodium iodide, reacted. This reaction time can be carried out expediently within wide limits by fluctuating. If the implementation z. B. in acetoman the reactants are carried out in an organic nitrile at reflux temperature, solvent, for example an aliphatic ketone, how is the reaction time I ¹ hours; it can bring together acetone and the reaction mixture can also be 3 hours,
heated to about 50 to 6O ⁰ C. Under these conditions, the reaction usually takes about one hour to complete the reaction with the orgagagen. The reaction mixture is then either the 21-phosphoric acid ester formed is cooled, diluted with water and the precipitate is isolated as the free acid, ie in the form of the monoester, and dried. Here, phosphoric acid is obtained, or in the form of the corresponding

Mono- or dialkali salt obtained. The extraction can be done by various methods. One method which has proven to be quite beneficial is to treat the reaction products with water to dilute, to distill off the organic solvent in vacuo and from the remaining aqueous solution to win the desired phosphate. This can e.g. B. by increasing the pH value to 4 to 11, preferably to 6 to 10, by adding an alkali hydroxide, such as sodium hydroxide, or an alkali carbonate, such as sodium carbonate, take place. Here the acidic monosteroid ester of phosphoric acid goes into the corresponding one Alkali salt over, and at the same time the excess silver precipitates as trisilver phosphate. The insoluble Material is filtered off. The salt of the steroid phosphoric acid ester can be extracted from the aqueous solution by freeze-drying and extracting the remaining anhydrous solid with a suitable organic solvents such as dry methanol. The methanolic Extract of the 21-phosphate salt can then be acidified with a strong mineral acid or preferably by treating with the hydrogen ion form a cation exchange resin can be converted into the free acid of the 21-phosphoric acid ester. The application an ion exchange resin is preferred over the use of mineral acids because this avoids contamination with inorganic salts. The free acidic 21-phosphoric acid ester is eluted, optionally concentrated and then by adding a suitable, non-polar one Solvent, such as diethyl ether or ethyl acetate, precipitated. The monosteroid 21-ester obtained in this way The phosphoric acid can be used as such in pharmaceutical preparations or in the desired Salts are transferred. Suitable neutralizing agents for this are sodium hydroxide, sodium methylate, Sodium carbonate, potassium hydroxide, ammonium hydroxide, calcium hydroxide or barium hydroxide. The steroid monosodium sphale can be used by neutralizing the free acid up to pH less than 7 and the disodium phosphates by neutralizing to pH of more than 7, preferably from 9 to 10, can be produced.

The following examples illustrate the process of the invention.

B e i s ρ i e 1 1

A suspension of 300 mg 11 / i, 17u, 21-trihydroxy-6 ", 16" -dimethyl-4-pregnen-3,20-dione-21-acetate. 700 mg of chloranil, 8.3 ml of ethyl acetate and 1.7 ml of acetic acid are heated to reflux temperature under nitrogen for 17 hours. The reaction mixture is diluted with 40 ml of ethyl acetate and filtered. The filter is washed in succession twice with 20 ml of ice-cold 10% aqueous sodium bisulfite solution each time and three times with 20 ml of ice-cold 5% aqueous potassium hydroxide solution each time and finally washed several times with 20 ml of ice water each time until neutral. The aqueous washing liquids are extracted with 50 ml of ethyl acetal and treated as described above. The combined organic phase is dried over sodium sulfate and concentrated in vacuo. The raw material is dissolved in benzene and chromatographed on 15 g of acid-washed aluminum oxide. Eluting with a mixture of 2 parts of chloroform and 8 parts of ether gives 11β, 17α, 21-trihydroxy-6,16a-dimethyl-4,6-pregnadiene-3,20-dione-21-acetate; F. = 208 to 210 ^° C. This product is then treated with a solution of potassium bicarbonate in aqueous methanol to give II /: J, 17a, 21-trihydroxy-6,16 "-dimelhyl-4,6-pregnadiene-3, 20-dione hydrolyzed.

Example 2

A suspension of 300 mg of 9a-fluoro-ll /) ', 17ri, 21-trihydroxy-6a, 16a-dimethyl-4-pregnen-3,20-dione-21-acetate, 700 mg of chloranil, 8.3 ml of ethyl acetate and 1.7 ml of acetic acid are left under nitrogen for 17 hours heated to reflux temperature. The reaction mixture is diluted with 40 ml of ethyl acetate and filtered. The filtrate is washed twice in succession with 20 ml of ice-cold 10% strength aqueous sodium bisulfite solution each time and washed three times with 20 ml of ice-cold 5% aqueous potassium hydroxide solution each time and finally several times washed neutral with 20 ml of ice water each time. The aqueous washing liquids are 50 ml Ethyl acetate extracted and treated as described above. The combined organic phase is over Dried sodium sulfate and concentrated in vacuo. The raw material is dissolved in benzene and added to 15 g chromatographed with acid-washed aluminum oxide. By eluting with a mixture of 2 parts of chloroform and 8 parts of ether give 9a - fluorine -II /?,! 7u, 21-trihydroxy-6,16a-dimethyl-4,6-pregnadiene-3,20-dione-21-acetate. This product is then converted to 9a-fluoro-U / ?, 17a, 21-trihydroxy by treatment with a solution of potassium bicarbonate in aqueous methanol - 6,16a - dimethyl - 4,6 - pregn adien-3,20-dione hydrolyzed; F. = 247 to 254 * C (with decomposition).

Example 3

A solution of 200 mg of the 11 / ί!, 17α, 21-trihydroxy-6,16u-dimethyl-4,6-prgnadiene-3,20-dione-21-acetate obtained according to Example 1 in 0.16 ml of acetic acid and 12 ml tert-amyl alcohol is mixed with 120 mg selenium dioxide and 2 drops of mercury. The mixture is refluxed under nitrogen overnight. The solution is filtered, washed with sodium bicarbonate solution, dried and concentrated. This product is chromatographed on acid-washed aluminum oxide. The adsorbate is eluted with mixtures of chloroform and ether that are increasingly richer in chloroform. The eluates are combined, evaporated to dryness and the residue is recrystallized from ethyl acetate. One receives 11/17 ”, 21-trihydroxy-6,16” -dimethy] -1, 4,6-pregnatriene-3,20-dione-21-acetate; F. = 179 to 183 ^: C. This product is then converted to 11p ', 17a, 21-trihydiOxy-6,16u-dimethyl-1,46-pregnatriene-3.20-dione by treatment with a solution of potassium bicarbonate in aqueous methanol hydrolyzed.

Example 4

A solution of 200 mg of the 9u-fluoro-1 Ifj.1 7a, 21-trihydroxy-6,16a-dimethyl-4,6-pregnadiene-3,20-dione-21-acetal obtained according to Example 2 in 0.16 ml acetic acid and 12 ml tertiary amyl alcohol is mixed with 120 mg selenium dioxide and 2 drops of mercury

puts. The mixture is refluxed under nitrogen overnight. The solution is filtered, washed with sodium bicarbonate solution, dried and concentrated. This product is chromatographed on acid-washed aluminum oxide. The adsorbate is eluted with mixtures of chloroform and ether that are increasingly richer in chloroform. The eluates are combined, evaporated to dryness and the residue is recrystallized from ethyl acetate. 9a-fluoro-II / 3.17a, 21-trihydroxy-6.16a-dimethyl-1,4,6-pregnatriene-3,20-dione-21-acetate are obtained; F. = 240 to 247 ^° C. This product is then treated with a solution of potassium bicarbonate in aqueous methanol to give 9a-fluoro-IIjS, 17a, 21-trihydroxy-6,16a-dimethyl-1,46-pregnatriene- 3,20-dione hydrolyzed.

Example 5

A solution, cooled to 0 ^° C., of 85 mg of the II / ?, 17a, 21-trihydroxy-6,16a-dimethyl-4,6-pregnadiene-3,20-dione in 0.5 ml of pyridine obtained according to Example 1 is mixed with 0.03 ml of methanesulfonyl chloride were added. The mixture is allowed to stand for about 1 hour at a temperature of about 0 ° C. _{The reaction mixture is then diluted with water for 2J} and the crystalline precipitate is isolated, washed with water and dried. It consists of 1 l / 3.17a, 21-trihydroxy - 6.16a - dimethyl - 4.6 - pregnadiene - 3.20 - dione-21-methanesulfonate.

A solution of 180mg ll / ?, 17a, 2J-trihydroxy-

40

sulfonate in 10 ml of acetone is mixed with 300 mg of sodium iodide. The mixture is refluxed for 1 hour heated, the reaction solution then cooled to room temperature and diluted with water. The crystalline precipitate is isolated, washed with water and dried. It consists of 21-iodine-11 p ', 17o-dihydroxy-6,16α-dimethyl-4,6-pregnadiene-3,20-dione.

320 mg of trisilver phosphate are mixed thoroughly with 0.1 ml of 100% phosphoric acid; the monosilver phosphate thus obtained is washed twice by decanting with diethyl ether in order to remove the unreacted phosphoric acid. 2.0 ml of acetonitrile are added and the mixture is heated to reflux temperature. The mixture is then treated with 21-iodine-11 / 3.17 "-dihydroxy-6,16α-dimethyl-4,6-pregnadiene-3,20-dione and heated to reflux temperature for 75 minutes in a nitrogen atmosphere with stirring. Then the reaction mixture is cooled to room temperature, treated with 2.0 g of ice-water and evaporate the acetonitrile in vacuo at a temperature below 25 ⁰ C. The pH of the resulting aqueous slurry is adjusted to 6.4 by adding 0.23 ml of saturated aqueous sodium carbonate solution. The precipitate that forms is filtered off and washed thoroughly with water. The filtered aqueous solution is combined with the washing liquids and subjected to freeze-drying, whereupon the residue is stirred seven times with 1.0 ml of methanol each time. The material which is insoluble in methanol is filtered off and the filtered methanolic solution is concentrated in vacuo to 0.2 ml and then 2.0 ml of ether are added. The precipitate which separates out is isolated, washed with ether and dried. It consists of 11 / ö, 17 «, 21-trihydroxy-6,16a-dimeth yl-4,6-pregnadiene-3,20-dione-21 -dihydrogen phosphate.

The anti-inflammatory action of the compounds produced according to the invention is determined according to the systemic granuloma test described in "Steroids", Vol. 1 (1963), pp. 163 to 165, namely the granuloma inhibition of 6,16a-dimethyl-I produced according to the invention ⁽ '- steroids are compared with that of analogous desmethyl derivatives and the corresponding 6,7-dihydro compounds.The values are shown in the table below, the test results being broken down so that they can be easily compared in connection with the later explanations under 1, 2 and 3 can:

Hydrocortisone (1 l / t?, 17a, 21-trihydroxy-4-pregnen-3,20-dione)

zl ° -hydrocortisone

löa-methylhydrocortisone

16a-methyl- / iMiydrocortisone

Prednisolone (1 l / ?, 17a, 21-trihydroxyl, 4-pregnadiene-3,20-dione)

6a-methylprednisolone

16a-methyl-zl ⁶ -hydrocortisone

6,16o-dimethyl- / 1 ⁶ -hydrocortisone ....

loa-methylhydrocortisone

6,16a-dimethyl-1 ⁶ -hydrocortisone

Prednisolone

6,16o-dimethyl-J ° -prednisolone

Systemic granuloma inhibition

0.5 1.1 4.08

3 3

4.08 40

1.1

40

71

The therapeutic superiority of the products that can be prepared according to the invention, namely of 6.16 "-dimethyll ⁶ -steroids, compared to the known agents hydrocortisone, prednisolone and 6α-methylprednisolone results from the following comparative considerations:

1. The introduction of the Δ "double bond in hydrocortisone weakens the systemic granuloma inhibition by half, while the introduction of the .. '!" Double bond in loa-methylhydrocortisone increases the inhibition approximately four-fold.

2. The introduction of a 6 <j-methyl group in prednisolone does not result in any appreciable increase in the inhibitory effect. In contrast, the introduction of the 6-methyl group with the formation of 6,16u-dimethyl- ^{I 6} -hydrocortisone increases the inhibition ten-fold compared to the 6-desmethyl analogue, 16a-methyl-I ° -hydrocortisone.

3. Although the introduction of an I ^e double bond in hydrocortisone weakens the inhibition by half and the introduction of the 6u-methyl group in prednisolone does not increase the inhibitory effect, the introduction of both a 6-methyl group and a! «Double bond brings one completely unexpected reinforcement of the inhibition:

a) Introduction of the 6-methyl-, il ⁶ -structure in lori-methylhydrocortisone to form 6,16u-dimethyl- l ° -hydrocortisone surprisingly results in a 35-fold increase in inhibition.

b) Introduction of the 6,16-dimethyl- I ° structure in prednisolone for the formation of 6,16a-dimethyl- ! '' - prednisolone leads to an approximately 25-fold increase in inhibition.

10

Compared to 9n-fluoro-16u-methylprcdnisolon (dexamethasone) the products of the process are characterized by the almost complete absence of diabetogenic substances Side effect.

Claims (5)

Claims: '5 1. Process for the preparation of U-oxygcnated 17a - hydroxy - 6.16a - dimeth yl - 4.6 - pregnadiene or -l, 4,6-pregnatriene-3,20-dione of the general formula CH ₂ R 30 CH ₃ in which R is a hydroxyl, acyloxy or phosphoric acid ester group, Ri is a hydroxyl or keto group, X is a hydrogen or halogen atom and in which the bond between carbon atoms 1 and 2 can be saturated or unsaturated, characterized in that in per se In a known manner, a corresponding 21-acyloxy-4-pregnene is dehydrated in the 6 (7) position with the aid of a substituted quinone, in particular chloranil, and the 21-acyloxy-4,6-pregnadiene obtained in this way, optionally with the aid of selenium dioxide, in 1 (2 ) -Stcllung is dehydrated, the obtained l ^{l (i} - or I ¹ · ^{4 β} -21-acyloxysteroid, if appropriate, alkali hydrolyzed and the 21-hydroxysteroid obtained is optionally converted into a corresponding 21-phosphoric acid ester. 2. The method according to claim 1, characterized in that one in the 11-position by Oxygen-substituted 17a, 21-dihydroxy-6,16udimethyl-4-pregnen-3,20-dione-21-aylate with the help of chloranil to the corresponding 4,6-pregnadiene-21-acylate dehydrated. 3. The method according to claim 1, characterized in that one obtained, substituted in the 11-position by oxygen .1 Tu, 21-di- yyyp
21-acylate is dehydrated with the aid of selenium dioxide to give the corresponding 1,4,6-pregnatriene-21-aylate. 4. The method according to claim 1, characterized in that one in the 11-position by Oxygen-substituted 9a-halo-17 «, 21-dihydroxy - 6.16 "- dimethyl - 4 - pregnen - 3.20 - dione-21-acylate dehydrated with the help of chloranil to the corresponding 4,6-pregnadiene-21-acylate. 5. The method according to claim 1, characterized in that one obtained in 11-Stcllung oxygen-substituted 9'-halogen-17a, 21-dihydroxy-6,16a-dimethyl-4,6-pregnadiene-3,20-dione-2) -aeylat with the help of selenium dioxide to the corresponding 1,4,6-Pregnatrien-21-aeylat dehydrated. Considered publications:
German Auslegeschrift No. 1 033 199;
U.S. Patent No. 2,891,079;
Journ. At the. Chem. Soc, 79, 1257/1258 (1957). 709 620/576 7.67 O Bundesdruvkerei Berlin