SU439089A3 - WAY OF OBTAINING 3-OXO-19-NOR-A4-STEROIDS - Google Patents

Description

This invention relates to a method for producing .19-nor-A steroids having biological activity.

There are known methods for producing 3-01Kco-19-NorA-steroids by reducing the aromatic ring A of steroids according to Birch.

Based on a known reaction, the proposed method for the preparation of 3-oxo-19-iHOip-A steroids of the general formula

R, R

where M is the remainder of the ring D steroid; Ri-los primary Ci-C5 alkyl; R, Hz, and lR is hydrogen or nivSHy alkyl, is that 10- (3-site-valued) -des-A-steroid of the general formula

H1 M

Yag

gset

R

where RI-R4 and M are as defined above; Rs is the residue O.Re, where Re is monocyclic lower aralkyl, hydrogen, acyl or 1kal of the general formula

-C-Ea

R9

ten

wherein RT, Rs and Rg are lower alkyl, are heated with an acid or, if Re is hydrogen, it is only heated or treated with an acid, resulting from cyclization, a compound of the general formula

20

25

where RI-R and M, as indicated above, are hydrogenated in the presence of a noble metal as a catalyst and a base to form a compound

where Ri-Rt and M are as defined above, this compound is o-treated with an amieOM of the general formula RNHs, where R is a hydroxy group, a lower alkoxy group, or a radical of the formula

./

-N.

Y

in which X and Y - lower al.kil, or salt, the compound obtained total mules

AT,

AT,

J

but w, n

E r

where RI is iR4, R and M are, as indicated above, selectively acidified to a compound of the general formula

where RI-R4, R and M are as defined above, the resulting compound is treated with an aqueous solution of the acid in an inert water-miscible organic solvent and the desired product is isolated by known techniques.

In the initial, intermediate and target products, M means half of the particular formula

where Z-carbonyl or a group of the general formula

™

in which - hydrogen or lower acyl; R is the city or lower aliphatic hydrocarbyl; t- 1 or 2.

The cyclization is usually carried out by heating in the range of m-ineric (sulfuric, salt | Na) or organic (without | H30l-, p-toluenesulphonic) acid, in the medium of hydrocarbon,

on the line | Mer benzene or toluene.

The hydrogenation is carried out predominantly in the presence of palladium on carbon and a base in an inert solvent, for example benzene or toluene, at room temperature and atmospheric pressure. Lower trialkylamine, for example triethylamine, is used as the base in the hydrirovININ stage.

The treatment with amino.m is carried out in an inert organic solvent, for example, pyridine, dime-lpOrmamide (DMF), tetrahydrofuran (THF), dioxane or isopropanol, preferably at room temperature. The amines of the formula RNHj are preferably used in the form of a salt with an inorganic, for example, sulfuric or hydrohalic, or

organic, naeri-meric uksuanoy, pro-pionic or sorrel, acid. Amines are most commonly used in which R is a lower alkyl alcohol, especially methyloxy group. The reaction is carried out preferably in the presence of a base, such as pyridine or trithiethylamine.

Chromic Acid, carbonic silver or opivnauer oxidation can be used as oxidizing agent.

The oxidation with chromic acid is carried out in a lower M, N-dialkyl alkanoyl amide, e.g. DMF, at O-25 ° C.

The cyclization into the target compounds is preferably carried out in a lower

alcohol, THF or dioxane in the presence of aqueous organic or mineral acid, of course sulfuric, hydrohalic, lower alkanoic, arylcarboxylic or arylsulfonic acid.

Zrimer 1. Benzene solution of 14.1 g (±) -6- (3-gret - butoxybutyl) - For, p-ethyl-4, b, 8.9.9a, 9 and -g1 x hydrohydro - 1H - 6eiH3 - e -indvn3, 7 - 2H, ZaH - dione is treated with 0.6 g of p-toluenesulfonic acid and heated for 4.5 hours

with reflux. After cooling and conventional treatment in a nitrogen atmosphere at 4 ° C and in the dark, (±) -2-weigh6a, p-ethyl-2, 3.4, 6.8.9, 9a, 9 & 10, M - decahydrocylcapent are obtained - (5.6) - naphtho - 2.1-6 - pyran7-6aH —one, t. Pl. 109-II6 ° C (twice from hetesan).

For the synthesis of the starting material, 71.5 g of 5XLor-2-1-pentanone is dissolved in 260 ml of ether and added over 50 minutes to

Suspensions 12 g of lithium aluminum hydride, stirred for 0.6 h at -30 ° C, added 5 ml of saturated sodium sulfate solution, filtered, washed the precipitate with ether, removed the ether in BaiKyyMe and isolated

5-chloro-2-1-poly-1-nanol, 2E8 g of which is dissolved in 500 ml of methylene chloride, 24 ml of forged sulfuric acid with 500 ml of methylene chloride are added, 1 l of liquid isobutylene is added and the mixture is kept at room temperature for 20 hours. The organic phase is washed with brine and with an aqueous solution of sodium bicarbonate, dried "with sulfonate sulfate, the solvent is removed in vacuum, and 5-chloro: 2-greg-butoxypent is obtained."

10 g of metallic mung bean is activated with iodine crystal, poured on Nago 20 ml of dry THF, 5 drops of dibromoethane are added, stirred for 15 minutes with a reflux condenser and 5-X1Loor-12-g / e-butoxy1-pentane is added in two stages. To the reaction mixture, 20 ml of ether, added with dissolved chlorine (63.5 r / Q50 ml), are added, and after that, the reaction is carried out (16 min-24 hours), the remaining 230 g are added for 1 hour. ml of solution, heated for 1 hour with a return cooler, smoothed and f-ilted.

The resulting Grignard reagent is added to pacTiBOpy 30 g of freshly tipped glutaraldehyde in 400 ml of THF at -05 ° C, stirred for 15 minutes at -25 ° C and 1 hour at 0 ° C, 050 ml of 20% -iHoro aqueous solution is added ammonium chloride, 1 o. hydrochloric acid to pH 4, extracted with ether and obtain 91 g of 6- (4-g / 5e-butoxy) -2-tetra-1HDRO (pyranol as an oil.

The resulting product was stirred with 650 ml of a 20% strength solution of sodium sulfate, hydrochloric acid and acetic acid to pH 6.6, 20% hydrochloric acid was added to pH 7.5, and stirred for 1 hour at 40 ° C. extract with ether, basify the aqueous layer with 20% sodium hydroxide and extract with ether. After extracting the ether in vacuo, pure 6- (4-t / 7et-butoxy) -2-tetrahydropyranol is isolated.

A solution of 4.6 g of 4- (4-tert-butoxy) 2 - tetrahydropyranol in 200 ml of THF is added to a solution of 300 ml of vinylmethyl chloride in THF for 20 minutes at 0 ° C, the mixture is stirred for 1 hour at room temperature, 200 ml are added ether and 100 ml of a 20% aqueous solution of ammonium chloride, extracted with ether and get 3,7-dioxy-11-g / 7g-butoxydod-Lhn in the form of a waxy solid.

41.3 g of 3,7-dio "si-11-g; oet-butoch1 sododets-1-enea is dissolved in benzene, 320 g of activated vivo" I | Mg magnesium in 1600 ml of benzene are contained in the suspension, 120 g ml of diethylamine, stirred for 20 hours at room temperature and filtered, the solvent was removed under vacuum, the remaining light brown oil was dissolved in ether and the extract was heated to 1N. hydrochloric acid. Sodium hydroxide is added to the extract, extracted with ether, evaporated to give 2- (2-diethylaminoethyl) -6- (4-tertbutoxypentyl) -2-tetrahydropyranol.

To a reflux-heated solution of 2-ethyl | Cyclo 1 penta-1,3-dione in 4ilO ml of xylene containing 220 ml of acetic acid

acids, added 42; 2 g of 2- (2-diethyl1Minoethyl) -6- (4-gre7-butoxypentyl) -2-tetrahydrapiranol, heated for 1 hour under reflux, OH cooled to room temperature, washed with water until the acetic acid disappeared in the solid water, evaporated in vacuo and get 3- (4-tertbutoxypentyl) - 6a, p-ethyl-2,3,5,6,6a, 8 - hexahydrocyclapent - - bvnopkran - 7 in the form of a light red oil, which is chromatographed on 1 , 2 kg of neutral alumina (1HF Art.) And produce 38.8 g of pure substance. A solution of 8.6 g of 3- (4-greg-buto-1XI1-pentyl) 6a, p - ethyl-2,3,6,6,6a, 8 - gaxahydro-cycloentant - f - benZ01pyran-7-1H-it in 80 ml of ether at -10 ° C dab1 is added to 4 g of lithium aluminum hydride in 200 ml of ether, stirred for 1 hour at room temperature, add

20 ml of a saturated solution of sodium sulfate, the precipitate is filtered off, washed with 160 ml of ether, the solvent is removed in vacuo and 3- (4-Greg-butoxy-1-pentyl) 6a is obtained, p is ethyl-2,3,5,6a, hexahydrodicloplopenta - f 1 -beN13opyran-7-1H-ol, so pl. 71 - 74 ° C (Gax-n).

6.3 g of 3- (4-tert-butoisipentyl) -bah.r-ethyl2,3,6,6, 6a, 8-hexahydrocyclopenta-benzopyran-7-1H-ol is dissolved in 100 ml

toluene containing 1.5 g of catalyst (palladium on carbon) is hydrogenated at atmospheric pressure and room temperature until the absorption of hydrogen ceases (1.05 mol), filtered, the filtrate is evaporated in a vacuum, and oily 6a, 9a-trans-3- is separated off (4-treh-butoxypentyl) - 6a, p ethyl - 2,3,5,6,6a, 8,9,9a - octahydrocyclopenta-L 1 -benzopyran-7-1H-ol, the purity of which is confirmed by thin-layer data

chromatography on silica gel.

36.9 g of 6a, 9a-trans-3- (4-greg-butoxypentyl) 6a, R-Etil - 2, 3, 6.6, 6a, 8.9.9 - octahydrocyclopenta-f 1 -benzopyran-7- 1H-ol dissolved in 700 ml of acetone, treated with 200 ml

3 n. sulfuric acid, incubated for two days at room temperature, diluted with brine, extracted with ether, evaporated in vacuo to give a mixture of 6a, 9a-trans-3- (4 tert-butoxypentyl) -6a, p - ethyl perhydrocyclopenta - / - benzopyran-4a, 7 -diola

and Za, 7a-trans-4- (3-tert-butoxy-3-hydroxyoctyl) -7a, p-ethylperhydroindan-1,5-dione.

4.65 g of the mixture obtained is dissolved in

200 ml of acetone, treated with 10 ml of chromic acid solution according to Jones, stirred for 30 min at room temperature, diluted with brine, extracted with ether, the solvent is removed in vacuum and get For, 7a-trans-4 - (7-tert-butoxy - 3 - oxooctyl) - 7a, p - ethyl perhydroindan-1,5-dione in the form of an oil, which gives one spot at thin-layer chromatography.

25.4 g of Za, 7a - trans - 4 - (7-tert-butoxy-Zoxooctyl) - 7a, p - ethyl perhydroindane - 1,5 dione are dissolved in 70 ml treg-butyl

alcohol, add 250 ml of treg-butyl alcohol and 1 g of sodium hydroxide powder, mix for 1 hour under nitrogen at 55 ° C, cool, treat with brine, extract with ether, remove solvent in vacuo, chromatograph on alumina (III st. act.), eluting with 15% - and 25% solutions of ether in petroleum ether, and get a transparent oily 10- (3greg-butoxybutyl) - 18 - methyl - 19 - nordes-A-androst - 9 - en - 5, 17 - diop, or 6- (3t-butoxybutyl) - Za, R-Etil - 4,5,8,9,9a, 9 & - hexahydro - LH - benz - -inden-3, ZaN - dione. After distillation, a colorless oily product is obtained, t. Kip. 180 ° C / 0.05 mm.

Example 2. 33.3 g (±) -2-methyl-6a, p ethyl - 2,3,4,6,8,9,9a, 9 & 10, 11 - decahydrocyclopenta - 5.6 - naphtho - 2 , 1-6 - pyran7-6aH-it in 300 ml of toluene is treated with 5 g of catalyst (palladium on coal) and 2.5 ml of triethylamine and hydrogenated at room temperature and atmospheric pressure until the absorption of hydrogen ceases (2.8 l, overnight ). The solids are filtered off, the solvent is removed in vacuo and (±) -2-methyl-6a is isolated, p-ethyl is 2.3.4, 4 & 5.6, 8.9.9a, 9 & 10, 11 - dodecahydrocyclopenta - 5.6 - naphtho - 2.1-6 - pyran - 7 in the form of an oil, which is a mixture of isomers in Cr (1: 1), t. Pl. 111 - 115 ° C (twice from hexane). After repeated recrystallization from hexane, a product enriched in one of the isomers is obtained, i.e. 118-122 ° C.

Example 3. 600 ml of liquid ammonia are saturated for 45 min with dry acetylene (passed through a trap at -72 ° C), 3 g of metallic potassium are added while continuously passing acetylene, transferred for 30 min, 8 g (±) is treated for 20 min - 2 - methyl - 6a, p - ethyl - 2,3,4,46,5,6, 8, 9, 9a, 96, 10, 11 - dodecahydrocyclopenta, 6 - naphtho - 2.1-6 - pyran-7 - 6aN - it, t. Pl. 118-122 ° C, dissolved in 120 ml of dry THF, transferred for 2 hours, 400 ml of ether were added and half of the ammonia was distilled off. 20 g of solid ammonium chloride are added to the reaction mixture and after 15 min 180 ml of water, the supply of acetylene is stopped, the resulting product is treated with ether and, after recrystallization from hexane, (±) -2-methyl-6a, ethyl-7a-ethynyl 2 are separated, 3,4,46, 5,6, 6a, 7, 8, 9, 9a, 96, 10, 11 - tetradecahydrocyclopenta - 5.6 - naphtho - 2.1-6 pyran - 7 - ol, t. Pl. 138-143 ° C.

. Calculated,%: C, 80.21; P 9.62.

С21НзоО2.

Found,%: C 80.19; H 9.48.

IR spectrum, CM-I: 3600 (-OH); 3300 (H – C C-); 1675 (C-C).

For the synthesis of the starting material, which can be carried out as in examples 1 and 2, 6- (3-gret-butoxybutyl) - Za, p-ethyl-4, 5, 8, 9.9 9a, 96-hexahydro-1H-benz - e - indene 3, 7 - 2H, 3fliH - dione is dissolved and 50 ml of ethanol, 0.3 ml of triethylamine and 100 mg of catalyst (5% palladium on carbon) are added, hydrogenated at room temperature 5 and atmospheric pressure to stopping the absorption of hydrogen, filtered, evaporated in vacuo and get 10- (3-t / 7g-butoxybutyl) - 18 - methyl - 19 - nor - de - A - androstan - 15,17 - dione, giving one spot at

10 thin layer chromatography.

500 mg of 10- (3-greg-butaksibutyl) -18-methyl-19-nor-des-A-androstan-15, 17 diones are dissolved in 25 ml of benzene containing traces of p-toluenesulfonic acid, heated for 2.5 hours cooler, wash the organic phase with an aqueous solution of sodium bicarbonate until no acid is present in the washings, remove the solvent in vacuo, recrystallize the residue from hexane and obtain (±) -2-methyl-6a, retil-2, 3, 4, 46, 5, 6, 8, 9, 9a, 96, 10, 11 — dodecahydrocyclopenta — 5.6 — naphtho — 2.1 —6 pyran-7-6aH —one, m.p. 111 - 115 ° C. Example 4. 1.5 g (±) -2-methyl-6a, p-ethyl .5 7a - ethinyl-2, 3, 4, 46, 5, 6, 6a, 7, 8, 9, 9a, 96, 10,11 - tetradecahydrocyclopenta - 5,6 naphtho - 2,1-6 - pyran-7-ol is dissolved in 5 ml of pyridine containing 0.25 ml of water, treated with 1 g of methoxyamine as chloro hydrate, kept at room temperature for 20 hours temperature (one spot at thin layer chromatography), treated with brine, extracted with dichloromethane, the extract is washed with water, dried in vacuum and obtained (±) -6- (3-hydroxybutyl) - 3-hydroxy - 5 7 - methoxyimino perhydro ZN-benz-e - indan in the form of a solid substance, etc. . 163-165 ° C (isopropyl ether). Calculated,%: C 73.09; H 9.76; N 3.87.

0 С22НзайМОз.

Found,%: C 73.23; H 9.81; N 3.81. Example 5. 1 g (±) -6- (3-hydroxybutyl) -3a, Rethyl-Sss-ethynyl-3-hydroxy-7-methoxyimino-perhydro-3N-benz-e-indan in 10 ml

5 DMF at 5 ° C is treated with a solution of 1 g of chromium trioxide in 10 ml of DMF, to which is added a solution of 5 ml of concentrated sulfuric acid in 3 ml of DMF, warmed to room temperature, stirred

0 1 hour, add dichloromethane and an aqueous solution of sodium bicarbonate, wash the organic phase with brine, 10 ml of 2% aqueous solution of sodium bisulfite, dry over magnesium sulfate, evaporate to dryness

5 in vacuum and get (±) -6- (3-oxobutyl) Za, p - ethyl - 7 - methoxyimino-Za-ethynyl-3oxyperhydro - 3N - benz - b - indan in the form of a vitreous substance. Example 6. 430 mg (±) -6- (3-oxobutyl) 0 Over, p-ethyl.-7-methoxyimino-Z-ethynyl-3-oxyperhydro-3N-benz-e-indane in 15 ml of methanol is treated with 7, 5 ml 4 n. hydrochloric acid, heated for 2 hours under reflux, treated with dichloromethane and

A whitish solid is isolated, which is chromatographed on silica gel (0.2-0.5 mesh), eluting with 5%, 10% and 20% solutions of ethyl acetate in benzene. In thin layer chromatography, the substance gives one spot; m.p. 185-195 ° C. After recrystallization from a mixture of hexane with acetone (together with the substance separated from the mother liquors), (±) -13 p-ethyl-17-ethnyl-17-oxy-gon-4-en-3-one is obtained.

Example 7. 1 g (±:) - a-methyl-6a, p-ethyl7a - ethinyl-2, 3, 4, 46, 5, 6, 6a, 7, 8, 9, 9a, 9b, 10, 11- tetradecahydro-cyclopenta-5,6-naphtho-2,1-b) pyran-7-ol in 5 ml of pyridine containing 0.1 ml of water and 0.5 g of N, N-dimethylhydrazine, incubated for 24 hours at room temperature, treated dichloromethane and get (±) -6- (3-hydroxybutyl) -3a, retil-Za-ethynyl-Zr-oxyperhydro-ZN benz-e-indan-7-one-S, N-dimethylhydrazone.

Example 8. Analogously to Example 5 (±) -6- (3-hydroxybutyl) - Za, p-ethyl-Sss-ethinyl Zr-hydroxyperhydro-3N-benz-e -indan-7on- | M, N-dimethylhydrazone is converted to ( ±) -13-ethyl-17a-ethynyl-17-hydroxy-gon-4-ene-3-one using (±) -6-6 (3-oxobutyl) -Za, p-ethyl-Za-ethinyl as the intermediate -3-hydroxyperhydro-ZN -benz-e-indan-7OH-N, N-dimethylhydrazone and (±) -6- (3-oxobutyl) -3a, p-ethyl-Za-ethynyl-3-hydroxyperhydro ZN-benz- e-indan-7-he.

Example 9. 10 g (±) -6- (3-gret-butoxybutyl) -3а, p-methyl-4, 5, 8, 9, 9a, 96-hexahydro-1H-benz-e-inden-3.7 - 2H, ZHH-dion is dissolved in 300 ml of benzene containing 500 mg of p-toluenesulfonic acid, heated under reflux for 3.5 hours, cooled, washed with an aqueous solution of sodium bicarbonate, the solvent is removed in vacuum and (±) -2- methyl-6a, p-methyl - 2,3,4, 6,8,9,9a, 96, 10, 11 - decahydrocyclopenta, 6 - naphtho - 2,1-6 - pyran-7-6aH - it in the form of oil .

IR spectrum, 1735 (cyclopentanone), 1645 (dienol ether).

UV spectrum, mmk: A, max 249 (e 17500).

To obtain the starting material, 28 g of (dz) -2 - (2-diethyl-aminoethyl) -6 - (-t-butoxy-pentyl) -tetrahydrofuran-2-ol is dissolved in 140 ml of xylene, 13.7 g of 2-methylcylloxyl is added. - 1,3 - dione, 280 ml of xylene and 140 ml of acetic acid, heated for 45 minutes under reflux, cooled, washed with water and an aqueous solution of sodium bicarbonate, dried over sodium sulfate, evaporated, chromatographed on 870 g of neutral alumina (III stage .act.) and get (±) -3- (4-tregbutoksipentyl) -6a,: p-methyl - 1, 2,3,5,6,6a-hexahydrocyclopenta - f 1 - benzopyran - in the form of oil .

Calculated,%: C 76.27; H 9.89.

Found,%: C 76.47; H 10.03.

UV spectrum, mmk: Amako 253 (e 17700).

23.1 g (±) -3- (4-gret-butoxypentyl) -6a, rmethyl-1, 2,3,5,6,6a - hexahydrocyclopenta 1 - benzopyran-7-8H - it is dissolved in 464 ml of THF at -10 ° C, 4.6 g of lithium aluminum hydride in 232 ml of THF is added to the suspension, stirred for 45 minutes at 0 ° C, treated with water, filtered, evaporated to obtain (±) -3- (4-greg-butoxypentyl) 6a , p-methyl-1,2,3,5,6,6a, 6a, 7.8 - octahydrocyclopenta - f 1 - benzopyran - 7p-ol, t. pl. 97-101 ° C (hexane).

. Calculated,%: C 75.78; H 10.41. Found,%: C 76.01; H 10.28. UV spectrum, mmk: Hmaks 252 (e 18700). A solution of 22.5 g (+) - 3- (4-gre7-butoxypentyl) - 6a, p-methyl - 1, 2.3, b, ba, 7, 8-octahydrocyclopenta - f 1 - benzopyran - 7p-ol 450 ml of toluene is hydrogenated in the presence of 3.4 g of catalyst (5% palladium on carbon) at room temperature and atmospheric pressure to absorb 1 mole of hydrogen, filtered, evaporated in vacuo to give (±) -3- (4-treg - butoxypentyl) - 6a, Rmethyl - 1,2, 3,5,6,6a, 7, 8,9,9a - decahydrocyclopenta - f 1 - benzopyran-7p-ol in the form of a light yellow oil, which after chromatography on a neutral oxide aluminum (III st. act.) strongly absorbs UV rays.

Calculated,%: C 75.38; H 10.93. Found,%: C 75.15; H 10.93.

IR spectrum (chloroform), cm-: 3625 (OH), 1680 (enol ether).

22.1 g (±) -3- (4-treg-butoxypentyl) - 6a, Rmethyl-1, 2, 3, 5, 6, ba, 7, 8, 9, 9a-decahydrocyclopenta - f 1 - benzopyran - 7p -ola in

220 ml of acetone are treated BY 1 ml. sulfuric acid, incubated for 3 hours at room temperature, most of the acetone is removed in vacuo at 35 ° C, extracted with ether, evaporated and (±:) - 3- (4 gret-butoxypentyl) - 6a is isolated, p is methyl perhydrocyclopenta - f 1 - Benzopyran-4a, 7p-diol in the form of a vitreous product. After chromatography on neutral alumina (III st. Act.), A substance is obtained, in

The IR spectrum of which showed absorption bands at 3625 (OH) and 1200 cm- (O-m-butyl) and no absorption bands characteristic of the enol ether were detected. Chilled to 15 ° C, a solution of 17.4 g (±) of 3- (4-greg-butoxypentyl) -6a, p-methyl perhydrocyclopenta-f 1 -benzopyran-4a, 7 rdiol in 700 ml of acetone is treated with a solution of 12.7 for 20 minutes chromium trioxide in 63.5 ml of sulfuric acid, mix

2 hours at room temperature, extracted with benzene to obtain (±) -gran-4- (3oxo-7-tert-butoxyoctyl) - 7a, p-methyl perhydroindan - 1.5 - dione as an oil. After molecular distillation at 195-

205 ° / 0.01 mm in the IR spectrum of the product absorption bands detected at 1735 (cyclopentanone); 1708 (cyclohexanone or alkyl ketone) and 1200 cm- (OH-butyl). Calculated,%: C, 72.49; H 9.95.

Found,%: C 72.21; H 10.00. A solution of 13.8 g {lb) -trans-4- (3-oxo-7-tertbutoxyoctyl) -7a, (3 - methylperhydroiidan1, 5 - dione in 38 ml of gret-butyl alcohol under nitrogen atmosphere is added to a solution of 544 mg of caustic soda in 136 ml of o-butyl alcohol, stirred for 1 hour at 55 ° C, treated with 1 ml of acetic acid, then with benzene, and benzene was removed in vacuo to give (±) -6 (3-g / 7g-butoxybutyl) - , p-methyl-4, 5, 8, 9, 9a, 9b. hexahydro - 1H - benz-e-i: nden3, 7 - 2H, ZaH - dione in the form of light yellow oil, which shows a strong absorption at Lmax 247 MMK (e 13000). IR spectrum, CM-I: 1730 (cyclopentanone), 1660 and 1600 (c clohexanone). Example 10. 8g (±) - 2 - methyl - 6a, g) methyl 2, 3.4, 6, 8, 9, 9a, 9b, 10, 11-decahydrocyclopenta - 5,6-naphtho - 2, pyran-7 was dissolved in 200 ml of toluene containing 1.5 ml of triethylamine and 1.5 g of catalyst (5% palladium on activated carbon), hydrogenated at room temperature and atmospheric pressure to absorb 1 mole of hydrogen, filtered, evaporated in vacuo and get (±) -2-methyl-6a, §-methyl - 2, 3, 4, 4b, 5, 6, 8, 9, 9a, 9b, 10, 11-dodecahydrocyclopenta - 5,6 - naphto - 2,1-pyran-7-6yN-it in the form of oil, which is purified on neutral alumina (III st. Act.). Calculated,%: C 78.98; H 9.42. Found,%: C 78.79; H 9.55. IR spectrum, CM-I: 1740 (cyclopentanone); 1680 (enol ether). Example I. 747 mg (±) -2-methyl-6a, p-methyl-2, 3, 4, 4Ь, 5, 6, 8, 9, 9a, 96, 10, P-dodecahydrocyclopenta - 5.6 - naphtho - 2.1-6) pyran-7- 6a H-one mixture of isomers C (1: 1) in 4 ml of pyridine is treated with 0.1 ml of water and 500 mg of methoxyamine hydrochloride, kept for 48 hours at room temperature, diluted with dichloromethane extract with brine, evaporate the extract in vacuo and allocate 954 mg (±) -6- (3-01 X.ibutyl) - Z, p-methyl-3,7 - dimethoxyimimine-perhydro - 3N - benz - ej-indane, which is chromatographed on , 50 g of silica gel (0.2-0.5 mesh), eluting with 10% and 20% solutions of ethyl acetate in benzene. The starting material is synthesized, as in examples 9 and 10, or 1.5 g (±) -6- (3-gregbutoxybutyl) - For, p - methyl - 1, 5, 8, 9, 9a, 9b - hexahydro-1H -benz-e-inden-3,. The ZOH-dione is dissolved in 25 ml of ethanol containing 0.15 ml of triethylamine and 200 mg of catalyst (5% palladium on activated carbon), is hydrogenated at room temperature and atmospheric pressure to the termination of the absorption of hydrogen, filtered, evaporated the filtrate in vacuum and get the racemate 6- (3-7ret-butoxybutyl) -3a, rmetilnergidrobenz - e -inden - 3,7-diop in the form of oil, the IR spectrum of which contains bands absorption at 1735, 1705 and 1200 This product is dissolved in 25 ml of benzene. containing 100 mg of α-toluenesulfonic acid, is heated under reflux for 4 hours, cooled, washed with brine, evaporated in a vacuum, the residue is filtered through a column filled with neutral alumina (stage III), and (±) -2-methyl6- is obtained a, | p-methyl - 2, 3, 4, 4Ь, 5, 6, 8, 9, 9a, 96, 10, 11 - dodecahydrocyclopenta - 5.6 - naphtho, 1-6) - pyran - 7 -. Example 12. 640mg (±) -6- (3-hydroxybutyl) Za, p - methyl-3,7 - dimethoxyiminoperhydro 3N-benz - indapa in 30 ml of xylene is treated with 3 g of silver carbonate, coated on celite, heated for 1 hour reflux under nitrogen, filter, wash with benzene, remove the solvent in vacuo and obtain an oily product, after crystallization of which pure (±) -6- (3oxobut .yl) -3a is separated from hexane, p-methyl-3, 7 - dimethoxyiminoperhydro - 3N - benz - e - indan, so pl. PO-111 ° C. Calculated,%: C 68.93; H 9.26; N 8.04. SgaNzgMzOd. Found,%: C 69.09; H 9.24; N 8.14. Example 13. 107 mg (±) -6- (3-oxobutyl) Za, p-methyl-3,7-dimethoxyiminoperperhydro 3N-benz-e-indan in 5 ml of methanol are treated with 1 ml of 6 N. hydrochloric acid, heated 2 , 5 hours under reflux, cooled, treated with dichloromethane and a saturated aqueous bicarbonate solution, the solvent is removed in a vacuum and after crystallization from a mixture of acetone and hexane, (±:) - 19-nor-androst-4-en-3 is obtained, 17-dione. Example 14. 3 g of 2-methyl-6a ,, p-methyl-2, 3, 4.46, 5, 6, 8, 9, 9a, 96, 10, 11 - dodecahydrocyclopenta - 5.6 - naphtho - 2, 1-6 - pyran - in 20 ml of ether at 10 ° C is added to the suspension 600 ml of lithium aluminum hydride in 25 ml of ether, stirred for 1 hour at room temperature, water is added, solids are filtered off, the solvent is removed and (±) - 2-methyl-6a, p-methyl-2, 3,4,46,5,6,6a, 7,8,9,9a, 9 & 10 11 - tetradecahydrocyclopenta-5, 6-naphtho-2, 1- 6 - pyran-ol-ol in the form of a vitreous substance, the IR spectrum of which contains absorption bands at 3600 (OH) and 1680 cm-1 (enol ether). Example 15. 837 mg (±) -2-methyl-6a, p-methyl-2, 3, 4, 46, 5, 6, 6a, 7, 8, 9, 9a, 96, 10, 11-tetradecahydrocyclopenta - 5, 6 -naphtho- 2,1-6 pyran-7p-ol is a mixture of isomers in Ca (1: 1) dissolved in 5 ml of pyridine containing 500 mg of methoxyamine hydrochloride and 0.2 ml of water, kept at room temperature for 48 hours. thin layer chromatography does not show any changes after 24 hours), treated with dichloromethane and brine, evaporated in vacuo, the oily residue is chromatographed over 60 g of silica gel (0, 0.5 mesh), eluting with 30-75% ethyl acetate in benzene, and isolating yl (±) -6- (3oxybuty l) -Sa, p-methyl-3p - hydroxy - 7 - labelCiiminoperhydro-3N -benz - e - indan in the form of a vitreous substance.

Example 16. 417 mg (±) -6- (3-hydroxybutyl) Za, p-methyl-3r - hydroxy-7-methoxyiminoperhydro 3N-benz-e - indan in 5 ml of DMF is treated with a mixture of 500 mg of chromium trioxide, 0.25 ml sulfuric acid and 5.5 ml of DMF, incubated for 2 hours at room temperature, diluted with water, saturated sodium bicarbonate solution, extracted with dichloromethane, the diketone is isolated as an oil, dissolved in 15 ml of methanol containing 7.5 ml of 4 N . hydrochloric acid, heated under reflux for 2 hours, diluted with brine, extracted with dichloromethane and (±) -19-nor-androst-4-en-3,17 was isolated as an oil, which, by chromatography on silica gel (0 , 2-0.5 mesh) gives one spot. With elution with 10% and 20% solutions, the substance with m.p. 145-155 ° C.

After recrystallization from dichloromethane-isopropyl ether, m.p. 155-157 ° C.

Example 17. 980 mg (±) -2-methyl-6a, p methyl - 2, 3, 4, 46, 5, 6, 8, 9, 9a, 9b, 10, And - dodecahydrocyclopenta - 5.6 - naphtho - 2.1 & pyran-7- 6aH-one in 5 ml of pyridine containing 0.1 ml of water and 550 mg of hydroxylamine hydrochloride, incubated for 24 hours at room temperature, extracted with dichloromethane and dioxime (±) -6- (3-hydroxybutyl) - After , - methyl perhydro-ZN-benz - e indan-3, 7-dione in the form of oil.

Example 18. 700 mg of dioxime (±) -6- (3oxybutyl) - Za, p - methylperhydro - 3N benzene-indan-3,7-dione are dissolved in benzene containing 4 ml of methyl ethyl ketone and 700 mg of aluminum isopropoxide, heated 24 hours under reflux, treated with an aqueous solution of sodium hydroxide, extracted with methylene chloride and dioxime (±) b- (3-oxobutyl) - Za, p-methylperhydro-3N benzo-eindan-3, 7-dione is separated.

Example 19. (±) - 2 - Methyl - 6a, p-ethyl2, 3, 4, 46, 5, 6, 8, 9, 9a, 9b, 10, 11-dodecahydrocyclopenta - 5.6 - naphtho - 2.1 - & -pyran-7 6aH -one, as in examples 2 and 11–13, is converted into 13 p-ethyl-gon-4-ene-3,17-dione using (±) -6- (3- oxybutyl) -Za, P - ethyl - 3,7-dimethoxyimino-perhydro-3N-benz-e-indane and (±) - 6- (3-oxobutyl) -Za, R-EHTIL 3, 7-dimethoxyimine-perhydro-3N-benzo e -indan.

Subject invention

The method of obtaining 3-oxo-19-nor-D4-steroids of General formula

RI

Ng

L

m y

rYr

Bt

where M is the remainder of the ring D steroid; -Ri is lower primary Ci-Cb-alkyl; Ra, Kz and R4 are hydrogen or lower alkyl, characterized in that 10- (3-substituted alkyl) is a desA steroid of the general formula

ten

where RI is (R4 and M are as defined above; RS is the ORe residue, where Re is monocyclic lower aralkyl, hydrogen, acyl or radical of the general formula

/ F7

-S-EZ in

25

wherein Ry, R8 and R9 is lower alkyl, is heated and treated with an acid or, if Rg is hydrogen, only is heated or treated with an acid, the compound of the general formula

35

40

where RI-R4 and M are, as indicated above, hydrogenated in the presence of a noble metal as a catalyst and a base to form a compound of the general formula

50

,

55 wherein RI-R4 and M are as defined above, the resulting compound is treated with an amine of the general formula RNH2, where R is a hydroxy group, a lower alkoxy group or a radical

60

X

/

General formulas in which X and Y are

lower alkyl, or its salt, the selected compound of the general formula rVVN N The compound is treated with an aqueous solution of the acid in an inert water-miscible organic solvent and the desired product is isolated by known methods.