DE1101416B - Process for the production of halogenated methyl steroids - Google Patents

Description

Process for the production of halogenated methyl steroids The main patent 1 043 333 describes a process for the production of methyl steroids which is characterized in that certain 20-keto steroids are used with the haloforms. Bromoform or chloroform in the presence of alkali metal alcoholates is converted to the corresponding 16-trihalomethyl steroids and the latter is then reduced in a manner known per se to the corresponding 16-methyl steroids, in which process other substituents in the molecule of the starting material and in particular a substituent which can be converted into a 3-keto group may be present, the latter, if desired, can be converted into the 3-position keto group in a manner known per se. The methyl steroids obtainable by the process of the main patent have industrially usable pharmacological properties.

It has now been found that one. too pharmacologically strong too effective, previously unrecognized steroids obtained when using the procedure of the main patent modified in such a way that one obtained in the first stage 16-Trihalogenmethlysteroide by appropriate choice of the hydrogenation conditions and selecting the halogens up to the appropriate ones, rather than up to the 16-methyl steroids Dihalomethyl or monohalomethyl steroids reduced.

Methods for the gradual partial exchange of individual halogen atoms of trihalomethyl compounds against hydrogen by means of reducing agents, in particular by using catalytically excited hydrogen appropriately selected catalysts are already known per se. When applying this Methods based on trihalomethyl steroids, however, should be noted that the most interesting steroids in addition to the trihalomethyl group in the molecule against others reducing agents sensitive groups, such as keto groups or carbon double bonds, may contain. It is therefore necessary to make the selection of the reducing Agents to take these named groups into consideration. After all, are Reduction methods of various degrees of effectiveness known in the steroid series, so that a suitable method is almost always available for the individual case will. In difficult cases, the desired goal can be achieved Appropriate choice of the trihalomethyl group to be introduced in the first stage facilitate.

In the case of the trihalomethyl steroids, for example, bromine atoms are more easily formed split off as chlorine atoms.

With a suitable choice of the reduction conditions one also has it next to it in hand whether one or two halogen atoms can be obtained from the trihalomethyl compounds wants to replace it with hydrogen.

As for the rest, it is of course also possible, just as with the procedure of the main patent, sensitive groups in the course of the implementations according to the invention To protect in the usual way or by methods of steroid chemistry known per se to be introduced into the molecule only afterwards. For example, a 3-permanent Hydroxyl group only after the reduction of the trihalomethyl group by subsequent Oxidation can be converted into the 3-keto group in a manner known per se.

The formula scheme gives, for example, an overview of those entering Reactions.

Example 1 16a-20,00g Tribrommethylpregnenolon (dargesellt according to Example 1 of patent 1,043,333) is hydrogenated in. 354 cc of methanol with 3.54 g of platinum oxide, after addition of 7.6 g of potassium acetate. The hydrogenation is stopped after uptake of 2 equivalents of hydrogen, the catalyst is filtered off and the solution is evaporated in vacuo. The residue is taken up in methylene chloride, washed with water and dried, and the solvent is distilled off in vacuo. The crude product is absorbed onto silica gel (100/1, 1120) using methylene chloride-carbon tetrachloride (3: 1) and chromatographed.

After recrystallization from isopropyl ether, the 16a-bromomethyl-pregnenolone melts at 177 to 178 ° C; UV absorption: s2.4 = 2960.

2.36 g of 16a-bromomethylpregnenolone are mixed with 100 ccm of absolute toluene and 20 cc of cyclohexanone heated to boiling and a few cc distilled off; 1 g aluminum isopropylate, dissolved in. 10 ccm of absolute toluene, is added dropwise and the mixture on for 45 minutes Heated to reflux. After the steam distillation, the residue becomes extracted with methylene chloride, washed with water, dried and evaporated in vacuo. 2.5 g of the substance are poured onto a column of diatomaceous earth with cyclohexene methylene chloride (3: 1), known under the trade name Celite, raised and chromatographed.

16a-bromomethylprogesterone melts after recrystallization from acetone at 140 to 142 ° C; UV absorption: E240mu = 14 500.

Example 2 600 mg of 45,16-pregnadien-3β-ol 20-one are added with the addition of one drop of phosphorus oxychloride in 15 ml of absolute benzene and 15 ml of 1,2-dihydropyran Stored at - {- 37 ° C for 16 hours. The solvent is then distilled off in vacuo and the residue is triturated with pentane and filtered off with suction.

3- (Tetrahydro-2-pyranyloxy) -45,16 -pregnadien-20-one melts, recrystallized from isopropyl ether, at 168 to 170 ° C; UV absorption: e239 = 9010 and s2.5 = 4770.

206 mg of the pyranyl ether are dissolved in 2.5 ml of absolute tetrahydrofuran and 0.3 ml of chloroform dissolved, and this solution is under nitrogen at -20 ° C within of 30 minutes to a solution of 350 mg of potassium tert-butoxide, 2.5 ml of absolute Tetrahydrofuran and 3 ml of tert-butanol were added dropwise with stirring. After that, under Warming to room temperature was continued for 10 minutes. It is then made with water diluted, extracted with methylene chloride and the methylene chloride phase with water washed neutral, dried over sodium sulfate and concentrated to dryness in vacuo. The remaining residue is recrystallized from hexane.

16a-Trichloromethyl-3- (tetrahydro-2-pyranyloxy-) 4 5-pregnen-20-one melts at 191'C (decomposition), UV absorption: a2.6 = 3560.

1,2 16a-Trichloromethyl-3- (tetrahydro-2-pyranyloxy) 4 5-pregnen-20-one are dissolved in 16 ml of methylene chloride and 45 ml of methyl alcohol with the addition of S drops conc. Dissolved hydrochloric acid and kept at room temperature for 1 hour. It is then diluted with methylene chloride and the methylene chloride phase with water washed neutral, dried with sodium sulfate and evaporated to dryness in vacuo.

16α-Trichloromethyl-45-pregnen-3β-ol 20-one melts recrystallized from isopropyl ether at 213 to 214 ° C. (decomposition); UV absorption: s2.5 = 3190-434 mg of 16a-trichloromethyl-45-pregnen-3ß-ol-20-one, 10 ml of ethanol, 250 mg of potassium acetate and 1 g of Raney nickel are saturated with hydrogen while shaking. The catalyst is then filtered off, diluted with methylene chloride, and the methylene chloride phase is washed with water and dried over sodium sulfate. The residue left by evaporation in vacuo is recrystallized from isopropyl ether.

16a-Chlormethyl1A, 1-pregnen-3ß-ol-20-one melts at 182 to 183 ° C; UV absorption: E2.5 = 3000.

Example 3 217 mg of 16α-trichlorinethyl-4 5-pregnen-3β-ol-20-one from F. 213 to 214 ° C (prepared according to Example 2) are in 10 ml of ethanol with 108 mg of potassium acetate and 50 mg of prehydrated platinum oxide with shaking until 1 equivalent is absorbed Hydrogenated hydrogen. The catalyst is then filtered off with methylene chloride diluted, the methylene chloride phase washed with water and dried over sodium sulfate. The residue remaining after concentration in vacuo is recrystallized from isopropyl ether.

16α-dichloromethyl-d 5-pregnen-3β-ol-20-one melts at 201 to 205 ° C; UV absorption: a2os = 2910.

1 g of 16a-dichloromethyl-d 5-pregnen-3ß-ol-20-one in 45 ml of absolute Toluene and dissolved with 9.6 ml of cyclohexanone and 486 mg of aluminum isopropylate, such as described in Example 1 for the preparation of 16a-bromomethylprogesterone, -after Oppenauer .oxidized, worked up and recrystallized from isopropyl ether.

16a-dichloromethyl-44-pregnen-3,20-dione melts at 168 ° C; UV absorption: E23. = 16,350.

Example 4 259 mg of 16a-trichloromethyl-3- (tetrahydro-2-pyranyloxy) -d 5-pregnen-20-one (prepared according to Example 2), 10 ml of ethanol, 6 ml of tetrahydrofuran, 108 mg of potassium acetate and 50 mg of prehydrated platinum oxide are absorbed until 1 equivalent of hydrogen is hydrogenated with shaking and then as in Example 3 described, worked up and recrystallized.

16a-dicblomethyl-3- (tetrahydro -2-pyranyloxy) -4 5-pregnen-17-one melts at 163 to 164 ° C; UV absorption: s2os = 3320.

Example 5 1.13 g of 16a-tribromopregnenolone are added to 20 cc of ethanol Addition of 0.22 g of potassium acetate hydrogenated with 80 mg of platinum oxide. After recording 1 equivalent of hydrogen (minus the self-absorption of the catalyst) takes place Work up as described in Example 1. The crude product thus obtained becomes from Recrystallized ethyl acetate.

16a-Dibromomethylpregnenolone melts at 202 bis with decomposition 204 ° C.

Claims (1)

PATENT CLAIM: Process for the production of halogenated methyl steroids of the general formula where R = H, OH, O-alkyl and D denotes the 5-membered ring of a steroid molecule and where X1 denotes one of the halogens chlorine or bromine, X, hydrogen or the same halogen as in X, by treating a, fl-unsaturated 20- ketosteroids with haloforms bromoform or chloroform, reduction of the resulting trihalomethyl steroids and optionally preparing a 3-keto group in accordance with patent 1,043,333, characterized in that the reduction by methods known per se is carried out partially.