SU453832A3 - METHOD OF PREPARATION Having applied this method, the authors obtained irregular and halogen-steroids of the Erengan series with valuable properties. The proposed method for obtaining the halo-15 steroids of the pregan series of the formula I \ = 2t L • Where Z is two aliphatic, aromatic or araliphatic hydrocarbon residues, or group ~ .C == Z— cycloalkylideic / / group and X is a fluorine or chlorine atom, consists in the fact that in the compound of formula II there are 'dH.FCHoF20, where RI and Rj are each free or etherified: 1 - or to the ether of oxygram or Ri together with R2 - group 2530 where RI and R2 have the indicated values epoxide ring cleaved action halo- geivodoroda HX, wherein X has the abovementioned meaning, or using an agent-releasing this galogeivodorod and the resulting halogen- gndrin simultaneously or sequentially dehydrated by treatment with hydrogen knslotoy halogen. - Google Patents

Description

According to the proposed method, 6a, 7i-epoxides II are treated with hydrofluoric acid or hydrochloric acid or agents that release these acids and are dehydrated and obtained as intermediate and 7a-oxp-6p-halogen-A-3-ketoi. When primeieiii koitseit) irovaiiyh hydrofluoric fire hydrochloric, acid iodhod boiling coff gels nairnmer in niz1PIH aliphatic carboxylic acids, such as ice ioy vinegar or nroiionovoy acid in ketones, such as anetone, in chlorinated hydrocarbons, nanr) 1mer chloroform or methylene chloride, or, on the other hand, in the ethers, such as iairnmer tetrahendrofuran, can be obtained directly from the mentioned eioxides L-b-halogen derivatives. When treating 6a, 7a-eioxides, the recovery of the auster of the halogen hydrogen chloride of the agent M1I is 7a-hydroxy-6p-halogoic compoundpiein. 7 (-a-hydroxy-6p-fluorosodiums) also receive ir: And the treatment of epoxides with hydrofluoric acid in tetrahydrofurag. From 7a-hydroxy-b (3-halogen compounds you can get L-6-halogen compounds by treating with hydrogen halide bluestamine aliphatic carbon dioxide acid, for example, in glacial acetic acid. The starting materials II are obtained by a well-known method, naimer by treating the corresponding β-preservatives with organic peracid, nairimer with phthalomonadic acid. 3-oxo-L-irreg) 1En1,1 in a known manner, naimer with hloranplom, tert, butaiol or amyl purificate or dlordhordiipibeisohioiioy in the presence of hydrochloric acid, or halogenate simple 3-iiol efra of compound II and leave halogen from 6-halogen derivatives, nairimer by the action of calcium carbonate or lithium carbonate in the presence of lithium halide in dimethylformamide Example 1. In a mixture of 400 ml of dioxane, 10 g of 3,20-dpox-16a, 17a-dioxn-21-fluoro-L-pre- 16, 17-aietoiida and 7 g of 2,3-dchlor-5,6-d1 cyabiobenzohioia are introduced within 15 minutes at the time of mixing and cooling with water hydrochloric acid. After 30 minutes, the mixture is filtered under suction and washed with toluene until the filtrate is washed with water, dried and evaporated in vacuo. The residue is recrystallized from a mixture of methylene chloride and ether, irichem and 3,20-dioxo-16a, 17a-diox-21-fluoro-D-irregnadien-16, 17 acetonend, t. Il. 256-257.5 ° C. To a solution of 11.53 g of the obtained diene in 720 ml of methylene chloride and mushroom was added and the displacement was 11.53 g of 86% h-chloro-benzoic acid. After 24 h, it is diluted with toluene, and the suspension is 2 n. sodium hydroxide solution and water, dried and evaporated in vacuo. The residue is dissolved in chloroform of methylene and filtered through 200 g of alumina (activity II). Then 6 liters of toluene / ethyl acetate mixture (9: 1) are additionally washed. After evaporation of the eluate in vacuo, the residue is recrystallized from a mixture of methylene chloride and ether; 7.01 g of the thus obtained 3,20-dioxo-6,7-epoxy-16a, 17-a-dioxy-21-fluoro-A-irregene-III, 17-acetonide is dissolved in 700 ml of chloroform, and then introduced at transferring and cooling with ice hydrochloric acid to saturation and then left to stand for 6 hours at room temperature. The reaction mixture is then poured with stirring into 1.2 l of saturated sodium bicarbonate solution, separated, further extracted with methylene chloride, washed with water, dried and evaporated in vacuo. The residue is dissolved in toluene and filtered through 210 g of alumina (activity II), additionally washing with 9 l of toluene. Repeated dissolution of the residue obtained after evaporation of the filtrate of methylene chloride and ether in vacuum gave 3.20 Dioxo-6-chloro-16a, 17a - dioxy-21-fluoro-D pregpadien-16, 17-acetonide, so pl. 238-241 ° C. Example 2. To a mixture of 10.14 g of 3,2-dioxo-16a, 17a-dioxy-21-fluoro-D-pregnen-16, 17-cycloienthanoipa and 300 ml of n. When the hydrochloric acid solution in dioxane is added, 7.5 g of 2,3-dichloro-5,6-dicyanobenzoquinoia are added at 17 ° C and washed additionally with 20 ml of dnoxane. After 30 mpn f.iltur on suction and additionally washed with toluene and methylene chloride. The filtrate is washed with water, 1% sodium hydroxide solution and again with water, dried and evaporated in vacuo. The residue is dissolved in toluene and filtered through 100 g of florisil and washed up to a solvent and a mixture of 3 l of toluene with ethyl acetate (4: 1). After evaporation of the filtrates in vacuo, 3,20-dioxo-16a, 17a-dioxy-21fluoro-L-iregnadia-16, 17-cyclopentanonide is obtained, which after recrystallization from methyl chloride and ether melts at 209-214 ° C. 5.9 g of 86% lg-chloro-benzoic acid was mixed with stirring to a solution of the resulting diethyl in 350 ml of methylene chloride and was added with stirring. After standing for 24 hours, the room temperature was diluted with toluene, washed with 2N. with sodium hydroxide solution, dried; they are evaporated in vacuum. The crude 3,20-dioxo-6,7-epoxy-16a, 17a-dioxy-21-fluoro-pregnan-16, 17-cyclopentanoide, thus obtained, is dissolved in 590 ml of chloroform, and then hydrochloric acid is added with ice cooling until saturation. After 6 hours at commacy, the temperature is diluted with methylene chloride and washed with a saturated sodium bicarbonate solution and water. The remainder of the organic solution dried and diarrheted in a vacuum is chromatographed on 250 g of flornzyl. From eluic mixture of toluene and ethyl acetate (49: 1)

3,20-d11oxo-6-chloro-16a, 17a-diox11-21-fluoro-L-prognadien-16, 17-uiiK get fractions. polyentanonide, which after repeated recrystallization from methylene chloride and ether, melts with 233-234 ° C .

Example 3. The original story can be obtained as follows.

A solution of 45 g of Sp-hydroxy-20-oxo-21-fluoro-L pregnadien and 48 g of aluminum iso-propylate R 1.5 liters of toluene and 360 ml of cyclohexaion are boiled for 2 hours in a stream of nitrogen. After cooling, the reaction mixture is poured into a saturated solution of segnete salt and extracted several times with toluene. The organic solutions are washed with a saturated solution of a segnetiate salt, dried, and evaporated in a vacuum, after which the high boiling part is distilled off under high vacuum at 80 °. Chromatography of the residue on 2 kg of florasyl is obtained from eluted with a mixture of toluene and ethyl acetate (9: 1) of a fraction of 3.20-dioxo-21-fluoro-L-pregnadiene, which after repeated dissolution from a mixture of methylene chloride, ether and a short track the ether melts at 163.5-165 ° C.

To a solution of 7 g of the resulting 3,20-dpoxo-21fluoro-D-presnadiene in 100 ml of benzene and 10 ml of pyridine were added, with ice-cooling, 5.8 g of osmium tetroxide and left to stand for 14.5 hours at room temperature. Then poured into a solution of 89.5 g of sodium sulfite, n 89.5 g of potassium bicarbonate in 875 ml of water and 575 ml of methanol, and additionally washed with 100 ml of benzene. After stirring for 5 hours, 3.75 L of chloroform is added and stirring is continued for 30 minutes. Then n is separated two more times with additional extraction with chloroform.

The organic phases are washed with a half-saturated sodium chloride solution, dried and evaporated in vacuo. After the residue was redissolved in methylene-acetone chloride, the crystallization solution was filtered in a solution of methylene chloride through 100 g of phlorisil and washed with a mixture of 3 l of toluene and ethyl acetate (4: 1). By crystallizing the residue, after evaporation in vacuum of the eluate, which is a mixture of methylene chloride, methanol and effr, 3.20 dioxo-16a, 17a-dioxy21-fluoro-Dpregnene is obtained. After recrystallization, it melts at 220.5-221.5 ° C.

To a boiling solution of 38.32 g of 3,20-dioxo-16, 17a-dioxy-21-fluoro-L-pregneia in 9.5 l of acetone was added 38 ml of concentrated hydrochloric acid. After three minutes of boiling, the mixture is left to stand at room temperature for 21 hours. It is then poured into 20 liters of half-saturated sodium bicarbonate solution and extracted several times with toluene. The organic solutions are washed with water, dried and evaporated in vacuo. By crystallizing the residue from a mixture of methylene chloride, ether and a small amount of pyridine, 3,20-dioxo-16a, 17a-dioxy-21-fluoroA-pregnenen-III, 17-acetonide, m.p. 260-263.5 ° C.

Example 4. The isomer used in Example 2 can be prepared as follows.

To a mixture of 10 g of 3,20-dpoxo-16a, 17a-d110xy-21fluoro-A-nperHeiia i and 100 ml of cyclopentanone were added to a mixture of 0.5 ml of 70% hyperchloric acid. After 20 minutes, everything dissolves, then after 80 minutes, it is poured into 200 ml of Hacbimeinioro sodium bicarbonate solution, extracted with methylene chloride, washed with water, dried and heated under vacuum. Dissolved in a mixture of toluene and ethylene acetate (4: 1), the residue is filtered through 100 g of phlorisil and additionally washed with the same mixture of solvents. 3.20-dioxo-16i, 17a-D1Uxy-21-fluoroL-pregie11-16, 17-cyclopentanoid, which melts after re-recrystallization from methylene chloride and ether at 218-229 ° C.

PRIORITY AND RESPONSIBILITY

Method for obtaining halogen-steroids of the pregnane range of formula I

B.,

where RI and Ro are each free or etherified into a complex or in a growing oxy group, PLI Ri together with Ro-gruii

ABOUT

Rde Z-two aliphatic, aromatic or araliphatic hydrocarbon-like resid-cyc .uiphilidene 50 ka, or gruyaa

c z

Va bruii and X is a fluorine or chlorine atom, characterized in that in the compound of formula II,

where RI and R2 are 11. the indicated values are split by the epoxy ring by the action of a hydrogen halide of the formula HX, where X has the indicated values, or the help of an agent,

dividing this hydrogen halide, and is prepared to be dehydrated by treatment with a halogen-halo hydrn, simultaneously or with a nasolodic acid.

453832