SU679147A3 - Method of producing dextorotatory homosteroids - Google Patents

Description

(54) METHOD FOR OBTAINING PRIMARY HOMOSTEROIDS

I

The invention relates to the method of milling: hormone action of new right-spinning homrosteroids having the general formula

ORl7ay3 j l7aot

H

where the dotted lines in ring A denote possible C — C bonds, R is hydrogen or methyl, R is oxo or, if Ring A is unsaturated, oxo (aH, -OH) nli (aH, / 3-0- acyl), and - hydrogen, C, -C 10 - alk1 "c benzyl, cyclohexylmethyl, acyl, tetrahydropyranyl or cyclopentenyl, and R is hydrogen, lower alkyl, ethinyl, vinyl.

The use of the well-known method of interaction of the keto group with the organometallic compounds I, makes it possible to obtain new dextrorotating homosteroids of the formula I with pharmacological properties.

The purpose of the invention is to expand the range of steroid compounds that have pharmacological properties.

The goal is achieved by the described method, in that the right-handed homo-steroid of the formula

II

where B, R and the dotted lines in ring A have the above meanings,

reacting with metal organics with a compound giving the residue R, such as methyl or acetylide, when temporarily protecting the 3-keto group, the resulting product containing the Pa / C-hydroxy group is isolated in the south, or sterilized to form an ether or ester.

Example. 15 g of the programa of homoandrost-4, 16-diene-3.17a-dione is dissolved in 150 ml of methanol, then boiled without air access together with 8.1 ml of nHpHjOHHa for 10 minutes under reflux. The reaction solution is cooled to -10 ° C. The crystallized enamine is filtered, dried in high vacuum at 20 ° C. 16.1 g of pure 3- (1-pyrolidinyl) -0-homoandrosta-3,5, 16-triene-17a-one are obtained. M.p. 207-21p ° C, UV spectrum: € 279 19500J 6277 13000, {a) 5 ° 295 °., 16.1 g of this enamine are dissolved in 750 ml of absolute tetrahydrofuran and added dropwise in 15 minutes stir the solution of 8 g of lithium aluminum hydride in 750 ml of absolute ether with OS. After that, i still stirred at 0 ° C. Then 300 ml of humid ether are carefully added to it, after which another 40 ml of saturated sodium sulfate solution is added, another 10 minutes is stirred and the precipitate is filtered off. The filtrate is evaporated in vacuo to give 15.8 g of a substance, which is heated to 45 minutes with stirring and treatment with argon together with a mixture of 1000 ml of methanol and 200 ml of 2N. caustic soda solution. The reaction mixture is then poured into an ice mixture of 6 l of water and 200 ml of acetic acid and extracted three times with methylene chloride. The organic extract is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 650 g of silica gel. With the use of acetone-hexane (1: 1), 13 g of syrup 17aE-hydroxy-O-gomoandrost - 4,16-dil-3-one is obtained. T.PL. 183-185 ° C, UV spectrum: 6341 162000; | (a) |, n-7bL Getting the original substance. 18.1 g of 30-acetoxy-0-homohan; cust-5-en-17a-it solution n at 45 ° C under argon atmosphere in 800 ml of methanol. To this solution, 25.3 g of copper-P bromide is added, then heated for 18 hours under reflux. The reaction mixture is cooled to 35 ° C, filtered, and the residue is thoroughly washed with chloroform. The combined filtrates are poured into 1.3 liters of water containing 100 g of salt and 500 g of ice. After this, trice 1 is extracted with chloroform. The organic phases are washed with a solution of boiled salt, dried with magnesium sulfate and evaporated in vacuo. 19 grams of pure 17a-bromo-3 hydroxy-0-homoandrost-5-ene-17a-one are obtained, which is used directly in the next step. 35.1 g of calcium carbonate are weighed into 290 g of dimethylacetamide. The treatment with argon distills off 40 ml. dimethylacetamide, then 18.7 g of 17a-bromo-3-oxy-O-homoandrost-5-17a-it was added for 20 minutes, after which the mixture was boiled under reflux for 30 minutes .. cooled to 60 ° C and filter the precipitate. The filtrate is poured into 1.25 liters of water containing 450 g of ice and 170 g of salt. It is extracted three times with methylene chloride, the extracts are washed with 1N. hydrochloric acid and water, dried with magnesium sulfate and evaporated in vacuo. 14.7 g of crude product are obtained, which is treated with a small amount of active carbon in dissolved form in 170 ml of ethyl acetate. After filtering the solution through Speedex Decalite, concentrate to a volume of 50 ml and allow to crystallize. 11.7 g of pure starting material is formed. M.p. 190-193 ° C, UV spectrum: 1300, (a) Y -177 ° (C 0.1 in dioxane). a) 50 g of 3 hydroxy-0-homoandrost-5,16-diene-17a-it is dissolved in 1 liter of cyclohexanone and 3 liter of toluene. 400 ml of solvent are evaporated from this solution. The solution is then cooled to 80 ° C and 60 g of aluminum tert-butylate are added. Stirring and treating with argon are heated for two and a half hours with a reflux condenser and water separator. The solution is concentrated in vacuo to approximately 200 ml, poured into an ice-cold mixture with 1500 ml of water and 50 ml of concentrated hydrochloric acid and extracted with methylene chloride. The organic extract is washed with water, dried with sodium sulfate and evaporated in vacuo. After that, dried in high vacuum with. The residue is recrystallized from acetone (hekeane) to give 40.7 g of pure protracted homoandrost-4.16 daen-3, 7a-dione. M.p. 193-194C, UV-spectrum: exsb 21500; (a) + 60 ° (C 0.1 in dioxane), b) 1 target 17a / 3-hydroxy-O-homoandrost-4,16-diene-2-one in 60 ml of pyridine and 60 ml of acetic acid anapride for the nights were kept at room temperature, then the solvent was removed in vacuo, and the residue was re-installed from acetone-hecan to give 6 g of pure 17a; 3-acetoxy-0-homoandrost 4.16-en-3-one. M.p. 165-167C, UV spectrum: ej4o 17000; (a) 5 + 91 ° (C 0.1 in dioxane). Similarly, with the use of the corresponding acid anhydride, the following can be obtained: 17a propionoxy-O-gomoandrost-4, 16-dien-3-one (t.Sh1.139-140 ° C), .17a) 3-butyroxy-0- homoandrosta-4, 16-dyo n-3-one (t.pl.117v) In a solution of 2g 17a / -oxn-0-homoandrost-4,16-dien-3-it in 20 ml of pyridine within 15 min. 2 ml of veschacetyl chloride are added, then the mixture is heated to 60 ° C for 5 hours. The mixture is poured into water and extracted with methylene chloride. The organic extract is washed with dilute hydrochloric acid, sodium bicarbonate solution and water until neutral, dried with sodium sulfate and evaporated in vacuo. The residue is chromatographed. on silica gel. Upon elution with g-xane-acetone (9: 1), 1.7 g of pure 17a | 3-phenyl acetoxy-D-homo-androst-4,16-daen-3-one is obtained. M.p. 135-136 ° С (from acetone-hexane), UV spectrum: € 540 17200; (+108 (C 0.1 in dioxane).

Similarly, the following compounds are obtained using the corresponding acid chloride:

17a undecanoyl-O-homo-androsta-4,16-diene-3-oHj amorphous; 17100; (a) y + 80 ° (C 0.1 in dioxane);

17a0-heptanoyloxy-D-homoandro-4,16-dien-3-one, oily; (a) jj + 88 ° (C 0.1 in dioxane);

17a phenoxnacetoxy-D-homoandrosta-4,16-dnen-3-one, T.11L. 174-P6 ° C.

d) 1g 17a hydroxy-O-homoidrosta-4,16-die-3-one is dissolved in 40 ml of absolute benzene, then 10 ml are distilled off. In the remaining solution, a solution of 5 mg of p-toluenesulfonic acid in 10 ml of benzene and 0.6 ml of dihydropyran is added, keeping the mixture then for 30 minutes at 1 F at room temperature.

The solution is washed with sodium bicarbonate solution to neutrality water, and suigate sodium sulfate K is evaporated in vacuo. The residue was cross-linked from ether-hexane to give pure 17aE-tetrahydropyranyloxy-O-homoandrost-4, 16-diene-3-one, m.p. 137-, UV spectrum; e14o 16650, (a) V ° (C 0.1 in dioxane).

e) A solution of 2g 17a -oxy -) - homoandrost-4,16-dien-3-one in 40 ml of cyclopentanone-diethyl ketal is heated to 120 ° C for 6 h. The reaction solution is evaporated to dryness in vacuo, the residue is chromatographed over 40 g of alumina of the second degree of activity. With benzene, 1.2 g of pure 17aE-cyclopenteshoxy-0-homoandrost-4, 16-dien-3-one was isolated. T.roi. 135137 ° С (from methanol), UV spectrum: Сгдо 17200 (о) У 100 ° (С 0.1 in dioxane)

Example 2. Under the conditions of examples a and 16, 17a acetoxy-O-homo-anrost-1, 4 16-triene-3-one, T.rui is obtained. 222-224 ° C, UV spectrum: e, 44 14800, (a) / + 53 °.

Example A 70 ml of a solution of methyl lithium in ether, while stirring, is added a solution of 3 g of 3,3-dimethoxy-0-homo-5a-alfost-16-en-17a-it in 20 ml of tetrandrafuran and 20 ml of ether for 30 minutes. The solution is stirred at room temperature overnight and then prepared in the usual way. 3.2 g of crude product are obtained which is dissolved in 50 ml of adeton, after

a solution of 1 g of p-toluenesulfonic acids in 5 ml is added. water. The mixture is kept at room temperature for 2 hours, then water is added and extracted with methylene chloride. After chromatography on silica gel, a pure 17a hydroxy-17aa-methyl-0-homo-5a-androst-16-ene-3-one is obtained from the residue. M.p. 2L-214 ° С (а) ° 52 ° (С 0.1 in dioxane).

Example 4. Under the conditions of Examples 1a and 1d, the following compounds were prepared:

Pa pentyloxy-0-gomoandrosta-4,16-diene-3-one. T. pl. 58-59 ° C (from methanol-water), UV spectrum: ej40 16700; (a) jj +112 (C 0.1 in dioxane);

17a / 3-n-decyloxy-0-homoandrost-4,16-dien-3-one, oily, UV spectrum: ej4o 166506 (a) + 94 ° (C 0.1 in dioxane);

17a benzyloxy-D-homoandrost-4,16-rfkeH-3-one, T.Sh1. 39-141 ° C (from acetone-hexane). UV spectrum: Cj 16600, (a) U + 130 °;

17a p kpoheksh1metiy-O-homoandrosta-4,16-dien-3-one. T.SH1. 98-99 ° C. UV spectrum: € 24 670Gj (a) / + il2 °;

Example 5. To a solution of 3 g of lithium aluminum hydride in 400 ml of absolute ether, with a stirring and cooling to OC, a solution of 6 g of O-homo-androst-4, 16-diene-3.17a-dione in 100 ml of tetrahydrofuran and 100 ml is added dropwise. ether, then stirring the solution for another hour at about -5 ° C. Carefully add 300 ml of wet ether and then 10 ml of saturated sodium sulfate solution. The reaction mixture is stirred for another 15 minutes, then the precipitate is filtered off and carefully dusted with methylene chloride. The collected filtrates are evaporated in vacuo. The residue is chromatographed on 330 g of silica gel to give 4.1 g of pure 3ft 17a-dioxy-O-homoandrost-4, 16-diene. T. 158-162 ° C (acetone-Gissan): (a) ° + 23 ° (C 0.1 in dioxane).

A solution of 3 g of 3, 17a (3-dioxn-O-homo-anrost-4, 16-diene in 50 ml of pyridine and 50 ml of anhydride with xenuaic acid is kept at room temperature for 18 hours, then the solution is evaporated in vacuo, and the residue is recrystallized in methanol, to obtain pure 3, 17a (3-diszdetoksi-O-gomoandrosta-4, 16-diene T. pl. 115 - 116 ° C, (a).

Example 6. To a stirring solution (cooled to 0 ° C) of 3.5 g of lithium aluminum alumina in 420 ml of ether, 7 g of 3,3-dimethoxy-0-homo-5a-androst are added dropwise. -16-ene-17-one in 280 ml of ether. The reaction mixture is stirred at -5 ° C for 1 h, then carefully added 250 ml of water-saturated ether (250 ml). This nooie is stirred for 15 more minutes.