SU147589A1 - The method of obtaining dl-19-nor-D-homotestosterone and its 17a-alkilanalogov - Google Patents

Description

It is known that some 19-norsteroids and their derivatives have a high anabolic activity (the ability to stimulate the synthesis of proteins in the body) and at the same time have a weak androgenic effect.

It is proposed to prepare yME-nor-D-homstestosterone and its 17a-alkylano-logs, based on the available 3-methoxy-D1,3,5, (10), 8,14-D-homoestrapentaenone-17a. The latter is reduced with lithium aluminum hydride, the product of the reduction is selectively hydrogenated, reduced with potassium and lithium in liquid ammonia, and hydrolyzed in th / -19-nor-D-homote, Sterone. In a different way, 3-methoxy-A1,3,5, (10), 8,14-D-homo-estrapentane-17a is hydrogenated to 3-methoxy-A1,3,5, (10) 8-D-homoestratetetraenone-17a, and reduced potassium and lithium in liquid ammonia in the presence of alcohol and hydrolyze.-nor-D-homotestosterone.

To obtain 17a-methyl-19-nor-D-homotestosterone, 3-methoxy-D1, 3.5, (10), 8-D-homoestrateteraenone-17a is condensed with magnesium methyliodide in 17aa-methyl-3-methoxy-D1,3,5 , (10), 8-D-homoestratetraenol-17ar, which is reduced by potassium and lithium in liquid ammonia in the presence of alcohol and hydrolyzed.

To obtain 17a-ethyl-19-nor-D-homotestosterone, 3-methoxy-A1, 3.5, (10), 8-D-homoestratetetraenone-17a is condensed with acetylenide

lithium in liquid ammonia in 17a-ethynyl-3-methoxy-A1,3; 5, (10), 8-D-homoestrateteraenol-17a, which is then selectively hydrogenated, reduced by lithium and potassium in liquid ammonia, and hydrolyzed.

Synthesis of th / -19-nor-D-homotestosterone and its 17a-methyl and 17a-ethyl homologues is carried out using the following scheme:

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Example 1. A solution of 10 g of ketone 1 in 50 ml of absolutized tetragndrofuran is added to a stirred suspension of 1 g of lithium aluminum hydride in 10 ml of tetrahydrofuran for one hour, after which the mixture is stirred for another hour and decomposed, sequentially, 10 ml of ethyl acetate, 70 ml of water and 5 ml of concentrated hydrochloric acid. The aqueous solution is extracted with ether, the combined extract is dried with anhydrous magnesium sulfate and filtered. The filtrate is evaporated, and the remaining yellowish oil is crystallized by trituration with alcohol. 8.5 g of 3-methoxy-A1,3,5, (10), 8,14-D-homo-esterpetianool-7ap (P) with a melting point of 113-115 ° are obtained. From mother liquors, another 0.4 g of substance can be obtained with a melting point of 113 - And 5 °.

Example 2. A solution of 5.2 g of carbinol P in 50. "L of absolutized tetrahydrofuran, previously hydrogenated before the absorption of hydrogen ceases, is hydrogenated in the presence of 0.3 g of lO / o-noro palladium on calcium carbonate until the absorption of one mole of hydrogen. The solution is filtered, evaporated and the residue is crystallized by trituration with alcohol. 4.6 g of carbinol P1 are obtained with a melting point of 116-117 °.

Example 3. In a four-necked flask equipped with a broom with a mercury gate, a gas supply tube, a thermometer and a tap, a sewed potassium hydroxide tube, 300 ml of ammonia are condensed and a solution of 1.5 g of carbinol P1 in the mixture is added at -40 ° 100 Zh. Of absolutized tetrahydrofuran and 100 mg of absolutized ether. After 10 minutes, 4.5 g of lithium (25 times excess) in small pieces was gradually added to the solution, the solution becoming blue-violet, and a bronze-colored plaque appeared on the walls of the flask. The absolute alcohol is then added dropwise to the bleaching (37 ml over 40 minutes), the ammonia is removed and it is decomposed with water. The aqueous layer is extracted with ether, the combined extracts are neutralized by the addition of dry ice, washed with water and dried with anhydrous magnesium sulfate. After the solvent is removed, the oily residue is crystallized by rubbing with alcohol. Obtain 0.8 g of 3-methoxy-D 2, 5, (10) -D-homoestradienol-17ar (IV) with a melting point of 128-1 ° -130 ° (pure carbinol has a melting point of 141-142).

Example 4 To a solution of 5 g of ketone VII in 700 ml of liquid ammonia and 140 ml of absolute tetrahydrofuran at -40 ° was added 7.9 g of potassium in small pieces. The mixture was stirred for one hour, after which 200 ml of absolute alcohol was added dropwise within 30 minutes, and then 20.7 g of lithium was added within an hour. Stirring is continued until decolouration (about an hour), 200 ml of absolute ether are added, ammonia is removed and the suspension is decomposed at a temperature of about-5 ° by adding 500 ml of water. After the usual treatment, 2.46 g of carbinol IV crystals with a melting point of 140-142 ° were isolated.

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Example 5. A mixture of a solution of 4.34 g of carbinol IV with a melting point of 140-142 ° in 45 ml of tetrahydrofuran, 130 ml of alcohol and 100 / hydrochloric acid (1: 2) is boiled for 15 minutes, cooled and poured into water. The precipitation is washed with water until it becomes neutral. reaction and then ether. 3.64 g of ketone V are obtained with a melting temperature of 138-HO. Chromatography on alumina from the ether / chloroform form fraction (2: 1) isolated pure ketone V with a melting point of 140-141 ° (from bepzol - petroleum ether).

Example 6. A solution of 500 mg of crude ketone V in 2 liters of pridin and 2 ml of propionic anhydride is left for a day and, after verifying that the acylation is complete (by chromatogram), is poured into water. 410 mg of 19-nor-D-homotestosterone propionate are obtained (VIa) with a melting point of 111-112 ° (from benzene to petroleum ether).

Example 7. To a solution of 500 mg of crude, ketone V in 10 ml of absolute benzene, 940 mg of phenylpropionic acid chloride and 0.9 ml of pyridine are added and left for about a day. After checking the completeness of the acylation, the solution is poured into water and extracted with ether. The extract is washed with a saturated solution of soda, water, dried with magnesium sulfate and evaporated. 510 mg of 19-nor-D-homotestosterone p-phenylpropionate (VI6) are obtained with a melting point of 118-126 °. After three-fold crystallization, 220 mg of pure ether was isolated with a melting point of 141 -143 ° (from benzene-petroleum ether).

Example 8. To a solution of magnesium methyl iodide (from 2 g of magnesium, 16 g of methyl iodide and 70 ml of ether), cooled to a temperature of 0 °, a solution of 6.2 g of 3-methoxy-D 1, 3, 5 was added in 25 minutes (( 0), 8 extratetraenone-17a (VII) in a mixture of 45 ml of absolute tetrahydrofuran and 100 liters of ether, stirred for 2.5 hours and the mixture was boiled for 30 minutes: Then the solution was cooled with ice, decomposed into 40 ml of 50 / o-hydrochloric acids, the organic layer is separated, and the aqueous layer is extracted with ether (4 times 50 ml). The combined extract is washed with a solution of soda, water and dried with magnesium sulfate. After filtering and distilling off the solvent, 7.7 g of a brown oil remain, which is dissolved with slight heating in 100 ml of a mixture of petroleum ether and benzene (7: 3). 40 g of alumina is added to the solution, stirred for 2 hours and transferred to a chromatography column with 240 g of alumina. By washing with petroleum ether and its mixtures with benzene (up to a ratio of 6: 4), 3.04 g of crystals are isolated, the crystallization of which from benzene gives 2.52 g (39Vi) of theoretical) carbinol XI with a melting point of 112-114 ° (analytically pure carbinol has a melting point of 4-115 °). Further leaching of mixtures of petroleum ether and benzene; (from 3: 7 and above), benzene and a mixture of benzene-ether (9: 1) gives 3.4 g of crystals, the crystallization of which gives 2.82 g (430/0 from the theoretical) of epimer Carbipol XI with a melting point of 117 -119 °.

Example 9. In the device described in example 3, at a temperature of -60-70 ° to a mixture of 500 ml of liquid ammonia and a solution of 2.3. Carbinol XI in 70 ml of absolute tetrahydrofuran and 150 ml of lb-salt ether, was added 4.3 g of potassium over 10 minutes and held for one hour. Then, 400 ml of absolute alcohol (50 minutes) is poured, after which 9.35 g of lithium (1 hour) is added. The mixture was kept for 2.5 hours at -bO-70 °, 300 ml of ether was added, the ammonia was allowed to evaporate and decomposed by cooling with 400 ml of water. The organic layer is separated and the aqueous layer is extracted with ether (4 times 50 ml). The combined extract is neutralized with carbon dioxide, washed with 20 ml of water and dried with anhydrous magnesium sulphate. After distilling off the solvents in vacuo, the remaining white crystalline mass (2.35 g) is dissolved by heating in 70 L of methanol, 5 ml of glacial acetic acid and 20 ml of hydrochloric acid IOVo are added, left to stand for an hour. t 5 min, poured into ice water and extracted with ether (5 to 60-70 ml). The extract is washed with a 10/20 soda solution, water, dried over magnesium sulfate, filtered, and evaporated in vacuo. Upon recrystallization of the yellowish residue from benzene, 0.86 g (39E / o from theoretical) of ketol XII with a melting point of 168-170 ° is obtained (analytically pure ketol has a melting point of 171-173 °).

Example 10. In the device, with the listan in example 3, 400 ml of ammonia are condensed, at -70 ° for 5-40 minutes 5-6 liters of dry acetylene are passed and 0.75 g of lithium is added. To a colorless solution of acetylide lithium obtained, a solution of 7.8 g of ketone VII in a mixture of 100 ml of absolute tetrahydrofuran and 100 ml of absolute ether was added over a period of 1.5 hours, and the oxidative pressure of acetylene was maintained for 2 hours at -70 ° and decomposed by adding 20 g of dry ammonium chloride and 200 ml of ether; Allow the ammonia to evaporate, add 300 ml of water and extract with ether (5 times 50 ml). Wash the extract with 20 ml of water, dry with mummy sulphate, filter and evaporate; Crystallization of the residue from methanol gives 6.1 g (72Vo from the theoretical) carbinol VIII with a melted temperature of 152-153 ° (analytically pure carbinol has a melting point of 155-156 °).

Example 11. 6.1 g of carbiol VIII are hydrogenated in 40 ml of absolutiroBa-ritioro tetrahydrofuran over 10 / o papladium on calcium carbonate. After the iogloschene, 900 ml of hydrogen (from theoretical) hydrogenation is practically stopped. The solution is filtered, the solvent is distilled off and the product is crystallized from methanol. Obtain 4.9 g (from theoretical) 3-methoxy-17a-ethyl-D 1, 3, 5, (10), 8-D-homoextratetraenol-17a (IX) with a melting point of 176-178 (analytically pure carbinol has a temperature of melt 81-i82 °).

Example 12. In the iribor described in example 3, at i-temperature -70 ° to a mixture of 300 ml of liquid ammonia and a solution of 1.7 g carb,

either 147589

IX in 50 ml of absolute tetrahydrofuran and 100 ml of absolute ether, 3.11 g of potassium is added over 10 minutes, after half an hour, 230 ml of absolute alcohol is added gradually (within 0.5 hours) and then within an hour 6.51 g of lithium. The mixture was left for 2 hours at a temperature of -70, 200 ml of ether was added and the ammonia was allowed to evaporate. The reaction mixture is decomposed by adding (with cooling) 400 ml of water, the organic layer is separated, and the aqueous layer is extracted five times with ether. The combined extract is washed with 20-30 ml of water, the solvent is removed, the residue (1.76 g) is dissolved in a mixture of 40 ml of methanol, 5 ml of tetrahydrofuran and 10 ml of 5 / hydrochloric acid 1 and syrup and boiled for 10 min The mixture is poured into water, extracted with ether, the extract is dried with dihydrogen, filtered and the solvent is heated. After the residue crystallizes from a mixture of cyclohexane-carbon tetrachloride (2: 1), 0.87 g (53% of theoretical) of ketol X with a melting point of 148-151 ° creep (analytically pure ketol has a melting point of 153-154 °).

The table shows the data of the physiological tests obtained on the 9-nor-homosteroids for anabolic and extragenic activity, and for the unit taken the corresponding activity of testosterone propionate. The tests were carried out according to the known method in rats.

The proposed method allows for the expansion of the range of 19-pore steroids with anabolic activity. Subject invention

The method of obtaining L-19-nor-D-homotestosterone and its 17a-alplanes, characterized in that, in order to obtain 19-nor-D-homosteroids, 3-methoxy-L 1, 3, 5, (10), 8, 14-D-homozstranentaenone-17a is reduced with lithium aluminum hydride, the product of reduction is selectively hydrogenated, reduced with potassium and lithium in liquid ammonia and hydrolyzed in d (/ -19-nor-D-homotestosterone; or 3-methoxy-A 1, 5 is hydrogenated , (10), 8, 14-D-homoestrapentenone-17a in 3-methoxy-D 1, 3, 5, (10), 8-D-homoestratetetraenone-17a, is reduced by potassium and lithium in liquid ammonia in the presence of alcohol and hydrolysis Coziness in L-sh-nor-D-homotestosterone; 3-methoxy-A 1, 3, 5, (10), 8-D-homoestratetetraenone-17a are condensed with magnesium methyl iodide in 17aa-methyl-3-methoxy-A 1,3 , 5, (10), 8-D-homoestratetraenol-17a | 3, reduced with potassium and lithium in liquid ammonia in the presence of alcohol and hydrolyzed to 17a-methyl-19-ior-D-homotestosterone; condensed with 3-methoxy-A 1, 3, 5, (10), 8-Dhomoestratetraenon-17a with lithium acetylide in liquid ammonia in 17a-ethynyl-3-methoxy-A 1, 3, 5, (10), 8-D-homoestratetraenol-17a, selectively hydrogenated, reduced with lithium and potassium in liquid ammonia and hydrolyzed in 17a-ethyl-19-nor- -gomotestosteron.

JVo 147589