DE1159441B - Process for the preparation of 16ª ‡ -Methyl-9ª ‡ -fluoro-í¸-corticosterones - Google Patents

Description

Process for the production of 16a-methyl-9a-fluoro-Al-corticosterones The invention relates to a process for the production of 16, -x-methyl-9x-fluoro-Al-corticosterone and esters thereof of the general formula wherein R represents a hydrogen atom or an acid residue.

These new products can find application in therapy due to their cortisone properties and in industry as intermediate products for further development of derivatives.

The production of 16, x-methyl-A'-corticosterone was taken elsewhere and esters of the same and stated that this product in comparison to other known cortisone derivatives has the advantage of only a low elimination effect of potassium salts.

The process according to the invention leads to new 16oc-methyl-9, x-fluoro-A 1-corticosterones in accordance with the attached reaction scheme, namely by adding 16tx-methyl-A 1-corticosterone-21-acetate (II) to is dehydrated in a known manner, the 3,20-dioxo-16x-methyl-21-hydroxy-pregna-1,4,9 (I1) -triene-21-acetate (111) obtained with a hypobromous acid-producing agent in a manner known per se Way, the bromohydrin (IV) formed is epoxidized in a manner known per se with the aid of a weakly alkaline agent, optionally with simultaneous saponification in the 21-position, to the 9,11-epoxide (VI) obtained, optionally after prior reacetylation in 21 is allowed to act and 10 + IO'C or at temperatures between --30 and + 5 ° C., the obtained 9- - hydrofluoric acid in the presence of dimethylformamide under cooling, preferably either by the method of the patent 1,122,943, at temperatures between-position, , t-fluoro-21-acetate (VII) according to known methods saponified and the resulting free 21-alcohol (I) esterified, if appropriate, by known methods.

The free 21-alcohol (I), like its ester, has a stronger one anti-inflammatory effect than the 16o.-methyl-A'-corticosterone used as starting material. It can be used especially for the treatment of acute and chronic rheumatic diseases, from root neuralgia or sciatica, from local or general inflammation, infectious Dermatoses, asthma, emphyses and fibroses can be used.

According to a preferred embodiment of the process according to the invention, the dehydration is effected in the 9.1 1-position with the aid of methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of pyridine and dimethylformamide and the bromohydrin is produced using N-bromosuccininud in the presence of dimethylformamide and perchloric acid, whereby the formate of the bromohydrin is obtained.

The alkaline treatment of the bromohydrin is preferably with sodium bicarbonate carried out, at the same time saponification of the ester function in the 21 position einti itt; in this case, the diene epoxide formed is reacetylated and then made the fluorohydrin. The 21-acetate obtained can be prepared using aqueous sodium bicarbonate be saponified in the presence of methanol to give the free 21-alcohol.

The following example explains the method according to the invention.

The melting points given are those determined on the Kofler bench instantaneous melting points. The temperatures are in degrees Celsius expressed.

The structural formulas of the starting, intermediate and end products of the invention Procedures are given in the reaction scheme.

Example Preparation of 16cc-methyl-9cc-fluoro-Al-corticosterone Step A: Preparation of 21-acetoxy-3,20-dioxo-16cc-methyl-, d 1, 4,1 (") - pregiiatrien (III) Dissolve 2g of 21-acetoxy-3,20-dioxo-11ß-hydroxy-16a-ynethyl-A1,4-pregnadiene (II) in a mixture of 6ccm dimethylformamide and 2.4ccm pyridine and added within 30 minutes with stirring and nitrogen atmosphere at one temperature of 20 '1.2ccm methanesulphonyl chloride The reaction mixture is then left for about 2 hours at 20', then it is poured into 100 cc of a mixture of ice and water.

The gummy residue is filtered off with suction, washed with water until the wash water is neutral and dried, and 1.09 g of compound III is obtained.

The crude product is dissolved in alcohol, treated with animal charcoal, filtered and the filter washed with alcohol. The combined organic phases are cooled on ice for about 1 hour, then the crystals obtained are filtered off with suction, washed with alcohol and dried. Recrystallization from aqueous acetone gives a product with a melting point of 162 '. [a] 'D' = +76.5 ' (c = 0.501, in acetone).

Analysis: C "H, 00, = 382.48 Calculated ... C 75> " / "H 7.9 0 /" found ... C 75.5 9 / " H 7.9 0 / ,.

The compound has not yet been described in the literature.

The starting compound II was prepared according to a process not claimed here otherwise, by starting from 21-acetoxy-16oc-methyl-3,11,20-trioxo-, d 1,4-pregnadiene, the keto functions in 3- and 20- Blocked position of this compound with the formation of the disemicarbazone, the keto function in the 11-position is reduced and then the 3 and 20 functions are released again.

Stage B Preparation of 21-acetoxy-9a-bromo-3,20-dioxo-Ilfl-formoxy-16 # x-methyl-A 1,4-prepregnadiene (IV) 2.5 g are dissolved at 20 to 25 minutes with exclusion of light 21-Acetoxy-3,20-dioxo-16oc-methyl-A l # 4, 9 (11) -pregnatriene (III) in 25 cc of dimethylformamide. Then 1.395 g of N-bromosuccinimide are added all at once at 20 to 25 minutes with stirring and while nitrogen is passed through. A solution of 1.395 cc of perchloric acid in 3.487 cc of water is added to the resulting solution within about 5 minutes.

A precipitate of the bromohydrin (IV) forms. The suspension is stirred under nitrogen for about 21⁄2 hours, then poured into 250 cc of a mixture of ice and water, stirred for 1 hour, the precipitate is filtered off with suction, washed with water until the wash water is neutral and dried. 3.15 g of compound IV of F. = 160 'are obtained. The analysis gives 16.1 "/, bromine (theory: 15.75 II / j. The product is not soluble in water. The compound IV has not yet been described in the literature. It can be used for the next process step without further purification will.

Step C: Preparation of 21-hydroxy-3,20-dioxo-9FL, 1 Eat-epoxy-16x-methyl-A 1, 4-pregnadiene (V) is suspended in 20 '3 g of the compound IV in 30 cc of methanol. The mixture is stirred and nitrogen is passed in for about 5 minutes, then a solution of 3 g of sodium bicarbonate in 30 cc of water is added. The suspension is refluxed with stirring and under nitrogen for about 20 minutes until the product dissolves. The reaction mixture is left under these conditions for approximately 45 minutes. It is then cooled to + 10 ' and 15 cc of 100% aqueous acetic acid is added in order to bring about a PIL value of 5.5 to 6 . Then add 45 cc of water and cool to -5 'for about 1 hour. Then the crystalline precipitate is filtered off, washed with water and dried at 400. This gives 1.68 g of 21-hydroxy-3,20-dioxo-9SS, LLSs-epoxy-16x-methyl-A 1, 4-pregnadiene (V ) from F. = 176 to 178 '. The product is insoluble in water.

The compound has not yet been described in the literature.

Step D: Preparation of 21-acetoxy-3,20-dioxo-9ß, 11ß-epoxy-16oc-methyl-A 1, 4-pregnadiene (VI) 1.68 g of compound V are dissolved in 6.72 cem pyridine, then 3.36 cc of acetic anhydride are added with stirring and under nitrogen at 25 '. The reaction mixture is held at 30 ' with stirring and nitrogen for about 3 hours. It is then poured into 100 cc of a mixture of water and ice and stirred for about 1 hour; then it is suctioned off, washed with water until the washing water is neutral and dried. The crude product is purified by dissolving it in aqueous dimethylformamide while hot, treating it with animal charcoal and crystallizing it in the cold.

1 '55 g of compound VI of F. = 177 to 178' are obtained. +79 ' -4 3 (c = 0.501, in chloroform).

The product is in alcohol, acetone, benzene, chloroform, methanol, Ethyl acetate and dimethylformamide soluble and insoluble in water and ether.

Analysis: C24H "0, = 398.48 Calculated ... C 72.33 0/0, H 7.59 0 /". 0 20.07 found ... C 72.10 / " H 7.911 / 0, 0 20.0 0 / ,.

The compound has not yet been described in the literature.

Step E: Preparation of llfl-hydroxy-21-acetoxy-3,20-dioxo-9cc-fluoro-16c # -methyl-A1,1-pregnadiene (VII) 1.223 g of compound VI are placed in 12.23 cc of a mixture of dimethylformamide and hydrofluoric acid (mixing ratio 3: 4), which is cooled to -30 4- 2 '. Complete dissolution occurs within about 15 minutes. The temperature is then allowed to rise to 0 to +5 ' and the reaction mixture is left at this temperature for about 2 hours. The solution is then poured into a mixture of 61 cem ammonia and 183 g of ice, left to stand for about 2 hours at 20 ', then filtered off with suction, washed with water until the wash water is neutral and dried.

The raw product is purified by dissolving it in alcohol in the heat, treating it with animal charcoal and letting it crystallize in the cold. It can be recrystallized from alcohol. 938 mg of compound VII from F. = 254 'are obtained. [x] 'D' = + 123 ' ± 2 (c = 0.5 0 /, in chloroform).

The compound is soluble in chloroform and hot acetone, in benzene sparingly soluble and in water, dilute aqueous acids and alkalis and in ether insoluble.

Analysis: C., H, 10, F = 418.49 Calculated ... C 68.87 Of, H 7.46 0/0, F 4.54 0/0; found ... C 68.6 0 / "H 7.4 0 /" F 4.5 l) / ,. UV spectrum: 2. "# in ethanol 239 m # t (s = 15 100).

The compound has not yet been described in the literature.

Step F: Preparation of 16 x-methyl-9-fluoro-x A 1-corticosterone (1) A suspension of 100 mg of compound VII, 2.5 cc of methanol, 50 mg Natriumbiearbonat and 1, 1, 5 cc Water.

Nitrogen is bubbled at 20 'for about 15 minutes, then the suspension is refluxed for about 45 minutes under nitrogen. The solution obtained is then cooled to 20 ', the pn value is brought to 5.5 by adding 250% strength aqueous acetic acid, the methanol is distilled off and an oily suspension is obtained. It is cooled to 0 'for about 1 hour, the crystals obtained are filtered off with suction, washed with water and dried. The crude product is obtained with a yield of about 90 "/, and it is recrystallized from ethyl acetate. A product of F. = 217 ' with 5.0 " /, fluorine (theory: 5.04%, fluorine) is obtained. . The compound is soluble in alcohol, acetone, chloroform and hot ethyl acetate, sparingly soluble in ether and benzene and insoluble in water and dilute aqueous acids and alkalis.

The compound has not yet been described in the literature.

Stage G: Preparation of ILß-Hydroxy-21-acetoxy-3,20-dioxo-9oc-fluoro-16ix-methyl-A1,4-pregnadiene. 1.5 g of the 16x-methyl-9x-fluoro-A1 obtained are dissolved -corticosterons in 10 cc of pyridine and adds 3 cc of acetic anhydride under a nitrogen atmosphere and with stirring at 27 '. The reaction mixture is kept under a nitrogen atmosphere and with stirring at 30 ' for 24 hours. It is then poured into 100 cc of a mixture of water and ice, stirred for 1 hour, filtered off with suction, washed with water and dried. The crude product obtained is purified by dissolving it in hot ethanol, treating it with animal charcoal and crystallizing it in the cold. After renewed recrystallization from ethanol, 1.6 g of pure 1 lβ-hydroxy-21-acetoxy-3,20-dioxo-9oc-fluoro-16ix-methyl-A 1,4-pregnadiene are obtained, the physical constants of which are similar to those of in Level E of the connection described in the example match. In the process according to the invention, the temperatures or the solvents can be varied within the limits known to the person skilled in the art.

The compound I obtained according to the method can by the action of a Acid anhydride or acid chloride in the presence of a tertiary base in a manner known per se Way to be converted into an ester. According to the procedure, come for this esterification in question the anhydrides or chlorides of saturated or unsaturated aliphatic or cycloaliphatic carboxylic acids and aromatic or heterocyclic acids Carboxylic acids, for example formic acid, acetic acid, propionic acid, butyric acid, Isobutyric acid, valeric acid, isovaleric acid, trimethyl acetic acid, caproic acid, ß-trimethylpropionic acid, oenanthic acid, caprylic acid, pelargonic acid, capric acid, Undecylic acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, stearic acid, Oleic acid, cyclopentyl, cyclopropyl, cyclobutyl and cyclohexyl carboxylic acid, cyclopropylmethyl, Cyclobutylmethyl, cyclopentylethyl and cyclohexylethylcarboxylic acid, the cyclopentyl, Cyclohexyl or phenyl acetic acid or propionic acid, benzoic acid, the phenoxyalkanoic acids, for example phenoxyacetic acid, p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid, 4-tert-butylphenoxyacetic acid, 3-phenoxypropionic acid, 4-phenoxybutyric acid, the Furan-2-carboxylic acid, 5-tert-butylfuran-2-carboxylic acid, 5-bromofuran-2-carboxylic acid, the nicotinic acids, the ß-ketocarboxylic acids, such as acetoacetic acid, propionyl acetic acid, Butyrylacetic acid, the amino acids such as diethylaminoacetic acid and aspartic acid.

Instead of corresponding carboxylic acid derivatives, esterification can be used also derivatives of sulfonic acids or those of phosphoric acids, sulfuric acids or Use hydrohalic acids.

Claims (2)

PATENT CLAIMS-1. Process for the preparation of 161x-methyl-9oc-fluoro-A 1-corticosterones of the general formula wherein R denotes a hydrogen atom or an acid residue, characterized in that 16oc-methyl-Al-corticosterone-21-acetate is dehydrated in a manner known per se, the 3,20-dioxo-21 - hydroxy - 16oc - methyl - j1 obtained, 4,9 (11) - pregnatrien-21-acetate with a hypobromous acid-supplying agent in a known manner, the bromohydrin formed in a known manner with the help of a weakly alkaline agent, optionally with simultaneous saponification in the 21 - position, epoxidized , allows hydrofluoric acid to act on the obtained 9,1 1-epoxide, optionally after previous reacetylation in the 21-position, in the presence of dimethylformamide with cooling, saponifies the obtained 9, - <- flu (, r-21-acetate according to known methods and the free 21-alcohol obtained is optionally esterified by known methods. 2. The method according to claim 1, characterized in that the dehydration is carried out in 9j 1-position using methanesulfonyl chloride in the presence of pyridine and dimethylformamide. 3. The method according to any one of claims 1 and 2, characterized in that the 3,20-dioxo-21-hydroxy-16, x-methyl-A1,4,9 (11) -pregnatriene-21-acetate obtained -with N-bromosuccinimide in the presence of dimethylformamide and perchloric acid -reacted, the bramhydrin being obtained in the form of its formate. 4. The method according to any one of claims 1 to 3, characterized in that the bromohydrin obtained is epoxidized with the aid of sodium bicarbonate, at the same time saponification of the ester function occurs in the 21-position, and that r-nan then reacetylated the free 21-alcohol obtained. 5. The method according to any one of claims 1 to 4, characterized in that the saponification of the 9, x-fluoro-21-acetate is carried out by means of aqueous sodium bicarbonate in the presence of methanol. Publications considered: Journ. At the. Chem. Soc., 80: 3161-3163 (1958) .