DE1131213B - Process for the production of new pregnane compounds - Google Patents

Description

Process for the preparation of new pregnane compounds The invention is a process for the production of 16x, 17x-ketals or 16x, 17x-acetals the 16x-hydroxy-6x-fluorine and 16x-hydroxy-6x-chlorine derivatives of hydrocortisone, cortisone, Prednisone, prednisolone and their 9a-fluoro and 9x-chloro derivatives and the 21-ester of these connections. The process products are characterized by their anti-inflammatory, glucocorticoid, thymolytic, antioestrogenic and antiandrogenic effects.

The new process products are obtained according to the following equation: X = fluorine or chlorine, X '= hydrogen, fluorine or chlorine, Y = H, β-hydroxy or oxo group, R and R1 = hydrogen or a hydrocarbon radical; Furthermore, an additional double bond can be present in the 1 (2) position.

According to the method, the starting materials of formula 1 are used with a Ketone, e.g. B. acetone, chloroacetone, diethyl ketone, acetophenone, or an aldehyde, z. B. formaldehyde, paraldehyde, benzaldehyde, furfural, under anhydrous conditions and in the presence of a catalyst. Copper sulphate, dry, serve as catalysts Hydrochloric acid gas or perchloric acid. The reaction is carried out in a suitable solvent, such as dioxane, or carried out in excess ketone or aldehyde.

For esterification in the 21-position, the compounds of the formula II in a known manner, for. B. with anhydrides of carboxylic acids in the presence of organic bases, e.g. B. pyridine implemented. To be mentioned are in particular the Anhydrides of carboxylic acids with 1 to 12 carbon atoms, which are saturated or unsaturated, straight-chain, branched, cyclic, cycloaliphatic or unsubstituted or substituted can be, e.g. B. by halogen or methoxy groups. Of the new 21 esters are primarily the acetates, propionates, butyrates, hemisuccinates, capronates, benzoates, Trimethylacetate, phenoxyacetate, cyclopentylpropionate, phenylpropionate and ß-chloropropionate to mention. For the procedural implementation are also suitable the 21-esters of the compounds of the formula; the 21-esters obtained can then be by alkaline hydrolysis, e.g. B. with sodium methylate in anhydrous methanol low temperature in a nitrogen atmosphere, convert into the compounds of formula II.

The starting materials can be prepared as follows 16x-Hydroxy-hydrocortisone or -cortisone or their 9x-halogen derivatives and 21-esters of these compounds are converted into the corresponding 3-ketals, the same are oxidized with an organic peracid such as phthalmono-peracid and the resulting 5x, 6x-oxido compounds with hydrohalic acid, e.g. B. HF or H Cl, split, optionally formed 5x-hydroxy-6ß-halogen compounds treated with a strong acid and, if desired, introduced a double bond in a conventional manner and in any order in the 1-position, hydrolyzed or ester groups free hydroxyl groups esterified. The introduction of a double bond in the 1,2-position is advantageous with dehydrating selenium compounds such. B. selenium dioxide, or microbiologically, e.g. B. made by incubation with Corynebacterium simplex. Example 1 To a mixture of 3 g 6x-Flour-d 4-pregnenlIß, 16x, 17a, 21-tetrol-3,20-dione, 200 cm- 'anhydrous dioxane and 10 g of paraformaldehyde are added to 24 g of anhydrous copper sulfate. The whole is stirred for 24 hours at room temperature and then filtered. The solution is concentrated in vacuo, diluted with water and the precipitate is filtered off. The product is extracted with methylene chloride, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. After the residue has been recrystallized from ethyl acetate, the cyclic 16x-17x- (formaldehyde) acetal of 6x-fluoro-16x-hydroxy-hydrocortisone with a melting point of 265 to 268 ° C is obtained; @, max 236 mp. and log e 4.18. Example 2 Following a procedure analogous to Example 1, the 21-acetate of 6x-fluoro-44-pregnen-llß, 16x, 17x, 21-tetrol-3,20-dione is converted into the 21-acetate of the cyclic 16x, 17x- ( 6x-fluoro-16x-hydroxy-hydrocortisone (formaldehyde) acetal converted; M.p. 241 to 244'C; @max 236 to 238 '; log e 4.15.

A suspension of 1 g of the above compound in 10 cm3 of absolute methanol is cooled to 0 'C and mixed with a solution of sodium methylate obtained by dissolving 60 mg of metallic sodium in 10 cm3 of absolute methanol. The mixture is stirred for 1 hour at O 'C in a nitrogen atmosphere and then poured into 100 cm 3 of a saturated aqueous sodium chloride solution which contains 0.3 cm 3 of acetic acid. The hydrolysis product is extracted with methylene chloride, washed with water, dried over anhydrous sodium sulfate and evaporated. After recrystallization of the residue, the cyclic 16x, 17oc- (formaldehyde) acetal of 6x-fluoro-16x-hydroxyhydrocortisöns, namely 16x, 17x-methylenedioxy-6x-fluoro-44-pregnen-lß, 21-diol-3, is obtained 20-dione, which is identical to the compound of Example 1. EXAMPLE 3 If the paraformaldehyde is replaced by paraldehyde in the preceding examples, the cyclic 16oa, 17a (acetaldehyde) acetal of 6oc-fluoro-16x-hydroxy-hydrocortisone with a temperature of 229 to 213 ° C is obtained; ,, max 235 m # t and log e 4.18, or its 21-acetate.

Following the procedure of Example 2, the corresponding 21-propionate can also be used instead of the 6x-fluoro-d 4-pregnen-Iß, 16a, 17x, 21-tetrol-3,20-dione-21-acetate. The 21-propionate of the cyclic 16a, 17x- (acetaldehyde) -acetal of 6x-fluoro-16x-hydroxyhydrocortisone obtained as an intermediate product is hydrolyzed to the hydroxyl group by treatment with sodium methylate as described in Example 2. Example 4 To a solution of 3 g of 6x-chloro-9a-fluorord1,4-pregnadiene-16x, 17a, 21-triol-3,1I, 20-trione in 500 cm3 in acetone distilled over calcium chloride, 30 g of anhydrous copper sulfate are added and the mixture was stirred for 48 hours at room temperature. The solid portion is separated off by filtration and washed with acetone. The filtrate and the acetone used for washing are combined, dried over anhydrous sodium sulfate and evaporated to dryness, finally in vacuo. The residue is purified by chromatography over 60 g of washed aluminum oxide, whereby the 16,17-acetonide of 6x-chloro-9oc-fluoro-41,4-pregnadiene-16x, 17x, 21-triol-3,11,20-trione is obtained (cyclic 16x, 17x-isopropyldene ketal of 6x-chloro-9x-fluoro-16x-hydroxy-prednisone); M.p. 215 to 218 ° C; Amax 238 m # t and log e 4.23. Example 5 A solution of 1 g 6x, 9a-dichloro-d4-pregnene-16x, 17oc, 21-triol-3,11,20-trione in 100 cm3 of acetone is cooled to O 'C, then with 15 cm3 of a saturated solution of dry hydrochloric acid mixed in acetone distilled over calcium chloride. The mixture is stirred for 10 minutes at 0 ° C. , 4.5 g of potassium carbonate in 100 cm3 of water are carefully added and then 500 cm3 of a saturated aqueous sodium chloride solution. The mixture is left to stand at 5 ° C. overnight. The precipitate is separated off, washed with a saturated sodium chloride solution and then with a little water, air-dried and then recrystallized from aqueous methanol which contains a few drops of pyridine. The 16x, 17x-acetonide of 6x, 9ca-dichloro-16x-hydroxy-cortisone is obtained in this way; M.p. 229 to 234'C; 2max 236 m (a, log e 4.14. Example 6) Into a stirred mixture of 3 g of 6x, 9a-Difluord 4-pregnen-1ß, 16x, 17x, 21-tetrol-3,20-dione and 20 cm3 of acetophenone 0.5 cm3 of 72 ° perchloric acid per hour at 0 ° C. The mixture is stirred for 1 hour at 0 ° C. After dilution with water, the organic phase is separated off, washed with water, dried with anhydrous sodium sulfate and the acetophenone in vacuo The residue is chromatographed over 60 g of neutral aluminum oxide, whereby the cyclic 16x, 17x- (methyl-phenyl) -ketal of 6x, 9x-difluoro-16x-hydroxyhydrocortisone is obtained; mp 271-274 ° C; Am. " 236 m # L / log e 4.18.

Example 7 A suspension of 4.2 g of 6x-fluoro-16x-hydroxyhydrocortisone in 150 cm3 of acetone, 0.3 cm3 of 72% perchloric acid is added while stirring. After 5 minutes everything has dissolved and after a further 30 minutes the reaction mixture becomes diluted with water and extracted with methylene chloride. The extract is made on top of this washed neutral, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is crystallized from acetone-hexane and the pure 16,17-acetonide is obtained 6x-fluoro-16x-hydroxy-hydrocortisone from 247 to 255 ° C; [x] D + 140 to 150 ° (Chloroform), Rmaz 236 m ... log e 4.17.

The 16,17-acetonides of 41,4-6x-fluoro-pregnadiene-11ß-16x, 17x, 21-tetrol-3,20-dione and its 9x-fluoro derivative can also be prepared in an analogous manner. Example 8 A mixture of 3 g of 41,4-6x-fluoro-pregnadiene-11β, 16x, 17x, 21-tetrol-3,20-dione, 70 cm3 of benzaldehyde and 0.1 cm3 of 70% perchloric acid is stirred for 6 hours at room temperature, the reaction mixture is then washed neutral with sodium bicarbonate solution, the excess benzaldehyde is evaporated off under reduced pressure and the residue is chromatographed on neutral aluminum oxide. 41,4-6x-fluoro-16x, 17x-benzylidendioxy-pregnadiene-llß, 21-diol-3,20-dione with a melting point of 278 ° to 282 ° C. is obtained; Amax 234, log s 4.18.

Example 9 When 3 g of 6x-fluoro-16x-hydroxyhydrocortisone are reacted, 70 cm3 of cyclohexanone and 0.1 cm3 of 70% perchloric acid are obtained according to the example 8 method indicated the 44-6a-fluoro-16cc, 17x-cyclohexylidenedioxy-pregnen-11ß, 21-diol-3,20-dione; 2maz 236 with., Log e 4.17.

Example 10 A mixture of 500 mg 6x-chloro-16x-hydroxyprednisone, 35 cm3 of methyl ethyl ketone and a drop of 70% perchloric acid are stirred for 1 hour at room temperature, the reaction mixture is then diluted with water and extracted several times with ethyl acetate, wash the extract neutral with water and evaporate reduced pressure to dryness. The residue is then processed in a known manner acetylated with acetic anhydride in pyridine, whereupon the methyl ethyl ketol des A '> 4-6x-chloro-pregnadiene-16x, 17x, 21-triol-3,11,20-trione-21-acetate from F. 234 to 238 ° C; @ .max 234 m # t and log e 4.19.

Claims (5)

PATENT CLAIMS: 1. Process for the preparation of new pregnane compounds, characterized in that compounds of the general formula where X is fluorine or chlorine, X 'is hydrogen, fluorine or chlorine and Y is an H, β-hydroxy or oxo group and which can have an additional double bond in the 1 (2) position, as well as 21-esters of the compounds mentioned with an aldehyde or ketone in the presence of a catalyst in a known manner and, if appropriate, the resulting compounds of the general formula in which X, X 'and Y have the above meanings and R and R1 are hydrogen or a hydrocarbon radical, esterified in a known manner in the 21-position or hydrolyzed 21-esters of compounds of the above formula. 2. The method according to claim 1, characterized in that that the ketone is acetone, chloroacetone, methyl ethyl ketone, diethyl ketone, cyclohexanone or acetophenone is used. 3. The method according to claim 1, characterized in that that the aldehyde used is formaldehyde, paraldehyde, benzaldehyde or furfural. 4. Process according to Claims 1 to 3, characterized in that the reaction is carried out in the presence of a catalyst, especially copper sulfate, hydrochloric acid gas or Perchloric acid. 5. Process according to claims 1 to 4, characterized in that a 16x-hydroxy-6x-fluorine or 16x-hydroxy-6x-chlorine derivative of hydrocortisone, cortisone, prednisone, prednisolone or their 9x-fluorine or 9x -Chlorine derivatives or their 21-esters are used as starting materials. References considered: U.S. Patent No. 2,701807; Journ. Amer. Chem. Soc., 73, p. 2463 (1951).