DE1177636B - Process for the dehydrogenation of 3-hydroxy -? - oestratrienes - Google Patents

Description

Process for the dehydrogenation of 3-hydroxy-A'.3,5 (1 (»- oestratnenen Es it was found that by the action of chloranil on 3-hydroxy-, 11-3,5 (10) -estratrienes, in particular on ustrone and ostradiol (3.17p) and the functional 17fl-OH derivatives of the latter, dehydro derivatives arise.

This is how the well-known A9 (I1) -dehydroestrone is obtained from Ostron, from estradiol as-dehydroestradiol (3.17ß) and not previously described from Ostradio1-17ß-n-valerianate the also not yet described A9 (11) -dehydroestradio1-17ß-n-valerianate.

This course of the reaction could not be foreseen. The process products can be used as medicinal products or as starting materials due to their therapeutic properties for the production of such use.

The A9 (11) dehydroestrone can be used for further processing z. B. by addition of hypobromous acid and subsequent dehalogenation in the already known Ilfl-hydroxyestrone. (The latter is in turn known to be a valuable starting material for the production of anabolically and androgenically highly effective 11-oxygenated 19-norsteroids, such as Ilfl-hydroxytestosterone, 17-methyl-llfl-hydroxy-19-nortestosterone and the like.). The yields of 11 fl-hydroxyestrone that can be achieved here are significantly higher than in the processes described so far.

Example 1 J9 (11) -Dehydroöstron 12g * estrone are dissolved in 100 times the amount of tert-butanol and boiled with 12 g of chloranil reflux for 6 hours. After filtration of the reaction solution, the tertiary butanol is distilled off and the residue is taken up in chloroform. After standing overnight, 6.5 g of tetrachlorohydroquinone are filtered off and the solution is washed several times with water. After drying over sodium sulfate, it is concentrated to dryness. The residue is recrystallized from chloroform (with charcoal). Yield: 8.2 g; M.p. 249 to 252'C; [al, = 198 ' (dioxane); UV: "-) 64 # 9950, t, 298 = 1530.

For cleaning, the substance is dissolved in methanol, made alkaline with 2N sodium hydroxide solution, acidified with 10% acetic acid and the substance is precipitated in water. The filtered off and washed crude product is recrystallized from methanol. 5.9 g of -A9 (11) -dehydroestrone are obtained; M.p. 248-253'C; [a], = -250.0 '(dioxane), UV. (Methanol): kv-cA # 13 400, E300 = 2560. Example 2 A8-Dehydroestradiol- (3.17β) 2.5 g of estradiol- (3.17β) are treated under the same conditions as in Example 1 with chloranil. After working up, 2.5 g of pale yellow crude product are obtained. According to UV (E277 = 14,600 ) and IR analysis, as-dehydroestradiol is present, which is still somewhat contaminated.

Example 3 A9 (11) -Dehydroöstradio1-17ß-n-valerate 2g Ostradio1-17fl-n-valerate are dissolved in 200m1 of tert-butanol and boiled with 4 g of chloranil reflux for 3 hours. Customary work-up and treatment with pentane give 1.69 g of A9 (11) -dehydroestradio1-17p-n-valerianate. UV: e2ffi 15 800.

Example 4 A9 (11) -Dehydroestrone 11.44 g of Ostrone are dissolved in 1000 ml of tert-butanol. After adding 22.8 g of chloranil, the mixture is refluxed under nitrogen for 16 hours. The solution is filtered and evaporated to dryness in vacuo. The residue is dissolved in 1000 ml of chloroform, and after standing for 2 hours with cooling, 19.4 g of tetrachlorohydroquinone are filtered off. The chloroform solution is washed several times with water, dried over sodium sulfate and concentrated to dryness in vacuo. After repeated recrystallization from methanol, 3.2 g of pure 19 (I1) -dehydroestrone are obtained; M.p. 248/252 / 254'C; [a) -D " = +297.5 ' (dioxane); UV (methanol): e263 - 18 250, e298 = 3060. Example 5 A9 (11) -Dehydroestrone-3-acetate 5g of ostrone-3-acetate are under treated with chloranil under the same conditions as in Example 14. After the usual work-up and repeated recrystallization from methanol, 1.85 g of pure A9 (11) -dehydroestrone-3-acetate; = +257.3 ' (dioxane); UV (methanol): a = 17,200, e29o = 2825.

Example 6 As-dehydroestradiol (3.17 μl) 4 g of CFstradiol (3.17 μl) are refluxed in 350 ml of tert-butanol with 8 g of chloranil under nitrogen for 16 hours. It is concentrated to dryness, the residue is taken up in chloroform and 7.2 g of tetrachlorohydroquinone are filtered off after standing for several hours while cooling with ice. The chloroform solution is washed several times with water and, after drying over sodium sulfate, concentrated to dryness. After treatment with pentane, 3.8 g of crude product are obtained. According to the IR and UV spectrum (en8 = 15,200), slightly contaminated As-dehydroestradiol- (3.17β) is still present.

Example 7 A9 (11) -Dehydroestradio1-17fl-oenanthate 59 Ustradio1-17β-oenanthate are refluxed in 450 ml of tert-butanol with 10 g of chloranil under nitrogen for 16 hours. After the usual work-up and treatment with pentane, 3.4 g of crude A9 (I1) -dehydroestradio1-17fl-enanthate are obtained; UV (methanol): e265 = 21,300.

Example 8 As-dehydro-17a-ethinyl estradiol 5g 17a-Athinylöstradiol 450M1 are heated in tert-butanol with 10 g of chloranil 16 hours under nitrogen at reflux. It is worked up as in Example 4. After two recrystallization from methanol, 2.4 g of A8-dehydro-17a-ethinyl estradiol are obtained; M.p. 177/179 to 180'C; [aj - 4.90 (dioxane); UV (methanol): A = 22 D 000. Example 9 A9 (I1) -Dehydroöstren-3-methyl ether 5g Ustron-3-methyl ether are boiled with log chloranil in 400 ml of tert-butanol for 16 hours under nitrogen at reflux. It is worked up as in Example 4. After repeated recrystallization from isopropyl ether, 1.9 g of A9 (11) -dehydroestrone-3-methyl ether are isolated; = +288 '(dioxane); UV m.p. (methanol): 142/144 to 145'C; = 18 0501 [al i 'e298 = 2970.

Claims (1)

Claim: Process for the dehydrogenation of 3-hydroxy-Al, 3.s (10) -estratrienes of the general formula x RO where X R2 C # 0 or C .OR1 R denotes hydrogen, acyl or lower alkyl, Rl denotes hydrogen or acyl and R2 denotes hydrogen or a saturated or unsaturated lower alkyl, characterized in that the 3-hydroxy-A1,3,5 (I0) oestratrienes mentioned are used in a manner known per se subjected to the action of chloranil, expediently in the presence of an inert organic solvent, preferably at temperatures between 70 and 120'C, and the resulting corresponding AI, 3.5 (10), 8- or A, 3.5 (10), 9 (I0) -ostratetraene separates.