DE1147580B - Process for the preparation of 5, 6-dichloro-3, 17ª ‡ -dihydroxy-16ª ‰ -methyl-allopregnan-20-one or of its 3-acylates - Google Patents

Description

Process for the preparation of 5, 6-dichloro-3,17 a-dihydroxy-16β-methyl-allopregnan-20-one or of its 3-acylates. The invention relates to a process for the preparation of 5,6-dichloro-3,17x-dihydroxy-16ß-methyl-allopregnan-20-one or of its 3-acylates, which consists in having a lower aliphatic carboxylic acid ester of the 5,6-dichloro-3-hydroxy-16,17-oxido-16ß-methyl-allopregnan-20-ons (I) with a strong Treated acid, the resulting mixture of 5,6-dichloro-3,17x-dihydroxy-16-methyl-15 (16) -allopregnen-20-one (II) and 5,6-dichloro-3,17a-dihydroxy-16-methylen-allopregnan-20-one (IIA) in itself catalytically hydrogenated in a known manner and the resulting 5,6-dichloro-3,17x-dihydroxy-16ß-methyl-allopregnan-20-one (11I) if desired into a corresponding 3-acylate by methods known per se (IV) transferred.

The conversions proceed according to the following equation In the structural formulas above, R denotes the radical of a lower aliphatic carboxylic acid and R 'denotes an acyl substituent. The starting material for the process according to the invention can be prepared as follows: A 3-acyloxy-5,16-pregnadien-20-one is reacted with diazomethane in an organic solvent to give 3-acyloxy-16a, 17x-methylenazo-5-pregnen-20-one . When heated, this compound forms 3-acyloxy-16ß-methyl-5,16-pregnadien-20-one, which is hydrolyzed with an alcoholic alkali to 3-hydroxy-16ß-methyl-5,16-pregnadien-20-one. The latter compound goes over by oxidation with hydrogen peroxide or a peracid in 3-hydroxy-16,17-oxido-16-methyl-5-pregnen-20-one, which leads to a 3-acyloxy-16,17-oxido-16- methyl-5-pregnen-20-one is acylated. The latter is then converted into the starting material used according to the process, namely a 5,6-dichloro-3-acyloxy-16,17-oxido-16ßmethyl-allopregnan-20-one, by reaction with chlorine in an organic solvent.

For the production of this starting material described here Patent protection not claimed.

In detail, the method according to the invention is carried out as follows: The 3-acyloxy-5,6-dichloro-16ß-methyl-16a, 17xoxido-allopregnan-20-one is through Treatment with a strong acid such as perchloric acid in a mixture of the compounds 5,6-dichloro-3,17a-dihydroxy-16-methyl-15 (16) -allopregnen-20-one and 5,6-dichloro-3,17a-dihydroxy-16-methylene-allopregnan-20-one transferred, both of which contain a double bond in the 16-position. The hydrogenation this mixture with hydrogen in the presence of a hydrogenation catalyst such as Platinum oxide, leads to the formation of 5,6-dichloro-3,17x-dihydroxy-16ß-methyl-allopregnan-20-one as the main product, which may be mixed in a known manner with a carboxylic acid anhydride, such as acetic anhydride, in pyridine to a corresponding 3-acylate, e.g. B. 5,6-dichloro-3-acetoxy-17x-hydroxy-16ß-methyl-allopregnan-20-one, is implemented.

The compounds prepared according to the invention are intermediates for the production of highly active anti-inflammatory steroids such as llß, 17.x, 21-trihydroxy-16ß-methyl-4-pregnen-3,20-dione and l 1β, 17x, 21-trihydroxy-16β-methyl-1,4-pregnadiene-3,20-dione.

For this purpose, the 5,6-dichloro-3,17a-dihydroxy-16ß-methyl-allopregnan-20-one via a corresponding 21-halogen compound to 5,6-dichloro-17xhydroxy-21-acyloxy-16β-methyl-allopregnan-20-one implemented. When chlorine is split off, this compound forms 3,17a-dihydroxy-21-acyloxy-16ß-methyl-4-pregnen-20-one, which is oxidized to 17oc-hydroxy-21-acyloxy-16β-methyl-4-pregnen-3,20-dione. The latter can be converted into 17a-hydroxy-21-acyloxy-16ß-methyl-1,4-pregnadien-3,20-dione by 1 (2) -dehydrogenation be transferred. In the two last-mentioned connections a 21-digit The thus obtained 17a, 21-dihydroxy-16β-methyl-4-pregnen-3,20-dione or 17a, 21-dihydroxy-16ß-methyl-1,4-pregnadiene-3,20-dione is microbiological Pathways with the formation of highly active compounds such as l 1ß, 17x, 21-trihydroxy-16ß-methyl-4-pregnen-3,20-dione and 11β, 17n, 21-trihydroxy-16β-methyl-1,4-pregnadiene-3,20-dione hydroxylated in the 11-position. Example A solution of 2.0 g of 5,6-dichloro-3-acetoxy-16,17-oxido-16β-methyl-allopregnan-20-one in 75 ml of dioxane and 20m1 2 n-perchloric acid is 48 hours at room temperature touched. The mixture is diluted with an equal volume of water and the precipitate filtered off and washed thoroughly with water. To remove one in less Amount of UV-absorbing by-product formed is the mixture of 5,6-dichloro-3,17ca-dihydroxy-16-methyl-15 (16) -allopregnen-20-one and 5,6-dichloro-3,17a-dihydroxy-16-methylene-allopregnan-20-one from methanol-petroleum ether recrystallized. The melting point of the mixture is after this treatment 194 to 198 ° C (with decomposition). The optical rotation of the mixture is -114 ° (CHC13).

A mixture of 1 g of these two unsaturated compounds is hydrogenated at 2.7 atm over 0.12 g of platinum oxide catalyst in 25 ml of purified dioxane. The catalyst is first pre-reduced in the dioxane. After the theoretical amount of hydrogen has been absorbed, the hydrogenation is terminated and the catalyst is filtered off. 100 ml of water precipitate the product, 5,6-dichloro-3,17x-dihydroxy-16β-methyl-allopregnan-20-one, which is filtered off and washed. Mp = 198 to 202 ° C. Recrystallization from acetone increases the melting point to 207 to 209 ° C. [x] δ5 = 69 ° C., c = 1 (CHCl3).

The product is converted into the 3-acetoxy compound using acetic anhydride and pyridine convicted.

Claims (1)

PATENT CLAIM: Process for the production of 5,6-dichloro-3,17x-dihydroxy-16ß-methyl-allopregnan-20-one or of its 3-acylates, characterized in that a lower aliphatic Carboxylic acid ester of 5,6-dichloro-3-hydroxy-16,17-oxido-16β-methyl-allopregnan-20-one treated with a strong acid, the resulting mixture of 5,6-dichloro-3,17x-dihydroxy-16-methyl-15 (16) -allopregnen-20-one and 5,6-dichloro-3,17x-dihydroxy-16-methylene-allopregnan-20-one in known per se Wise catalytically hydrogenated and the resulting 5,6-dichloro-3,17x-dihydroxy-16ß-methyl-allopregnan-20-one if desired with a carboxylic anhydride by methods known per se in a corresponding 3-acylate transferred.