RU2163606C1 - METHOD OF SYNTHESIS OF γ-LACTONE 3 OF (7α-ACETYLTHIO-17β-HYDROXY-3-OXOANDROST-4-ENE-17α-YL)-PROPIONIC ACID - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, pharmaceutical chemistry. SUBSTANCE: invention relates to the improved method of synthesis of potassium-preserving diuretic, namely, spironolactone (verospiron, aldactone) from available raw - sterols of vegetable and animal origin. Spironolactone [γ-lactone 3 of (7α-acetylthio-17β-hydroxy-3-oxoandrost-4-ene-17α-yl)-propionic acid] of the formula (I): γ is synthesized from androstendione or its derivative of the formula (II): 7α where 17β means carbonitrile; 17α means hydroxyl that is subjected for protection with

-3-ketosystem, methylenation at 17-keto-group with dialkylsulfonium methylide generated in situ from trialkylsulfonium halogenide followed by conversion of synthesized oxirane cycle to lactone cycle by formation of

-dienone structure, addition of thioacetic acid and isolation of the end product. Formation of R¹-dienone system is carried out after preliminary formation of lactone ring and simultaneous decarboalkylation by heating in aprotonic solvent in the presence of catalytic amount of saturated aqueous solutions of salts of strong bases and strong acids, selective functionalization of 6th position of steroid molecule using haloidation-dehydrohaloidation reactions. Then thioacetic acid is joined and the end product is isolated. Method ensures to avoid the formation of by-side products and resinification of reaction mass as result of carrying out reaction under mild conditions. EFFECT: improved method of synthesis, increased yield of main product. 9 cl, 12 ex

Description

 The invention relates to the field of chemistry, and in particular to methods for producing potassium-sparing diuretic, namely spironolactone (veroshpiron, aldactone) from available raw materials - sterols of plant and animal origin.

пропионовая кислота] формулы (I).Spironolactone [

propionic acid] of the formula (I).

является высокоэффективным диуретиком, имеющим целый ряд преимуществ по сравнению с другими диуретиками: не изменяет структуры почечного эпителия, не характеризуется диабетогенным действием, может применяться при гипокалиемии, вызванной другими диуретиками.

It is a highly effective diuretic that has a number of advantages compared to other diuretics: it does not change the structure of the renal epithelium, does not have a diabetic effect, and can be used for hypokalemia caused by other diuretics.

гидрирование тройной связи, лактонизацию и построение

структуры. Выходы на отдельных стадиях высоки и составляют 88-95% [1-11].Methods for producing spironolactone (I) include varieties of acetylene synthesis and further metallization of the ethynyl group and its carboxylation with preliminary protection

triple bond hydrogenation, lactonization and construction

structure. Yields at individual stages are high and make up 88-95% [1-11].

связи).In the known methods it is necessary to use two protective groups at different stages of synthesis: ethylene ketal (at the carboxylation stage) and enol ether (at the introduction stage)

communication).

 In addition, a significant drawback of these methods is the large-scale use of acetylene, the use of sodium hydride, butyllithium, a Grignard reagent as a metallizing agent, as well as the use of a palladium catalyst at the hydrogenation stage or the use of pressure in the case of a nickel-boride catalyst, which complicates the process.

 Another way to build a spironolactone molecule is based on the use of 17-spirooxyranes.

подвергают защите

метиленируют по 17-кетогруппе диалкилсульфонийметилидом, генирируемым in situ из триметилсульфонийбромида с последующим построением

структуры, превращением полученного оксиранового цикла в лактоновый, присоединением тиоуксусной кислоты и выделением целевого продукта [12].Closest to the proposed is a method for producing spironolactone of the general formula (I), which consists in the fact that androstenedione (AD) of the formula

protect

methyleneated at the 17-keto group with dialkylsulfoniummethylide, in situ generated from trimethylsulfonium bromide, followed by construction

structure, conversion of the obtained oxirane ring to lactone, addition of thioacetic acid, and isolation of the target product [12].

 In the known method, decarboalkoxylation is carried out at the last stage, and the ester group in the lactone ring, passing through several stages, can hydrolyze and form a by-product that reduces the yield of the main product. In addition, the decarboalkoxylation reaction is carried out under severe conditions: at high temperature and pressure in the presence of a strong acid.

 The technical result of the proposed method is to increase the yield of the main product by eliminating the formation of by-products and grinding the reaction mass, carrying out reactions under milder conditions.

пропионовой кислоты формулы (I)

заключающемся в том, что андростендион или его производное формулы (II)

где R¹ - карбонитрил, R² - гидроксил, подвергают защите

⁴-3-кетосистемы, метиленированию по 17- кетогруппе диалкилсульфонийметилидом, генирируемым in situ из триалкилсульфонийгалогенида с последующим превращением полученного оксиранового цикла в лактонный, построением

системы, присоединением тиоуксусной кислоты и выделением целевого продукта, построение

системы осуществляют после построения лактонного кольца и одновременного декарбоалкоксилирования путем нагревания в апротонном растворителе в присутствии каталитических количеств насыщенных водных растворов солей сильных оснований и сильных кислот, и последующей селективной функционализацией 6-го положения стероидной молекулы с помощью реакций галоидирования - дегидрогалоидирования.The technical result is achieved by the fact that in the method of obtaining

propionic acid of the formula (I)

consisting in the fact that androstenedione or its derivative of the formula (II)

where R ¹ is carbonitrile, R ² is hydroxyl, is protected

⁴ -3-ketosystems, methyleneation at the 17-keto group with dialkylsulfoniummethylide, genetically in situ generated from trialkylsulfonium halide with subsequent conversion of the obtained oxirane ring to a lactone one, by construction

system, the addition of thioacetic acid and the selection of the target product, construction

The systems are carried out after the construction of the lactone ring and simultaneous decarboalkoxylation by heating in an aprotic solvent in the presence of catalytic amounts of saturated aqueous solutions of salts of strong bases and strong acids, and subsequent selective functionalization of the 6th position of the steroid molecule using halogenation-dehydrohalogenation reactions.

где R³ - ацил, или алкил, или карбокси-ацил, или атом H, R⁴ - H или C₂H₅, а производное андростендиона формулы (II) с R¹ - карбонитрил, a R² - гидроксил получают путем взаимодействия АД с ацетонциангидрином.Moreover, androstenedione (AD) is obtained by microbiological oxidation of sterols of plant or animal origin of the general formula (III)

where R ³ is acyl, or alkyl, or carboxy-acyl, or an H atom, R ⁴ is H or C ₂ H ₅ , and the androstenedione derivative of formula (II) with R ¹ is carbonitrile, and R ² is hydroxyl obtained by the reaction of HELL with acetone cyanohydrin.

производного андростендиона формулы (II) можно осуществлять путем образования спирокеталей на основе этиленгликоля, или 2 - моно - или 2,2 - дизамещенных или незамещенных производных 1,3 - пропандиола, или пирролидиновых или морфолиновых енаминов или енолэфиров.Also protection

the androstenedione derivative of the formula (II) can be carried out by forming spiroketals based on ethylene glycol, or 2 - mono - or 2,2 - disubstituted or unsubstituted derivatives of 1,3 - propanediol, or pyrrolidine or morpholine enamines or enol ethers.

 In addition, dialkylsulfoniummethylide in situ generation from trialkylsulfonium halide is carried out in the presence of a strong base.

 Moreover, tert-butylates or hydrides or hydrated alkali metal hydroxides are used as a strong base.

 In addition, this generation can also be carried out in the presence of a phase transfer catalyst.

 In addition, quaternary ammonium salts in an effective amount are used as a phase transfer catalyst.

 As the quaternary ammonium salt, trialkylarylammonium halides can be used.

 In addition, in the halogenation reaction, dibromantin or N- or N-bromosuccinimide can be used as an agent, and dehydrohalogenation is carried out in an aprotic solvent using alkali and alkaline earth metal salts.

пропионовой кислоты (спиронолактона) формулы (I) осуществляется по следующей схеме:

где R⁵ и R⁶ - енолэфир или циклический кеталь, или енамин.Production method

propionic acid (spironolactone) of the formula (I) is carried out according to the following scheme:

where R ⁵ and R ⁶ - enol ether or cyclic ketal, or enamine.

 Androstenedione (AD), obtained by microbiological oxidation of sterols of plant or animal origin of the general formula (III), or its derivative (II), obtained by reacting AD with acetone cyanohydrin, is initially protected with 3-keto group to form enol ethers or cyclic ketals, or enamines (compound of general formula (IV). Then this compound is methyleneated at the 17-keto group with dialkylsulfoniummethylide generated in situ from a trialkylsulfonium halide in the presence of a strong base and kat interfacial transfer lyser (or without it) in an aprotic solvent.

The oxirane (V) obtained in 99% yield was converted to spirolactone (VII) by condensation with dialkyl malonate in the presence of sodium alcoholate, followed by decarboalkoxylation by heating the reaction product in an aprotic solvent at the boiling point in the presence of catalytic amounts of saturated aqueous solutions of salts of strong acids and strong bases. The 6th position is selectively functionalized using sequential bromination-dehydrobromination reactions, and allyl bromination reagents such as N-bromosuccinimide or N-bromoacetamide or dibromantine in an aprotic solvent are used for targeted bromination at C ₆ . The dehydrobromination reaction is carried out without isolation of intermediate product (VIII) in the presence of alkali or alkaline earth metal salts at a temperature of 60-80 ^° C. The spirodiene (IX) formed in 95% yield is reacted with thioacetic acid. The total yield of spironolactone (I), which meets the requirements of the pharmacopeia, is 45-50%, counting on sterols (III), or 70.2%, counting on derivatives of blood pressure (II).

The invention is illustrated by the following examples.
Example 1. Enolesterol AD (3 - methoxyandrost -3,5-diene -17-one).

To a solution of 19 g of trimethylorthoformate in 146 ml of methanol was added 62.5 g of HELL. The suspension is stirred for 15 minutes and 142 ml of a solution of 0.125 g of sulfosalicylic acid in a 26.74% solution of trimethylorthoformate in methanol are added slowly. The reaction mass is maintained at a temperature of 20 ... 25 ^o C for 1 h 15 minutes At the end of the exposure, the reaction mass is cooled to 10.. . 15 ^o C, slowly add 46.9 ml of acetone and incubated for 1 h at the same temperature. Then add 0.5 ml of triethylamine to a pH of 7-8, cool the reaction mass to 0 ... + 2 ^o C and add a solution of 1.52 g sodium hydroxide in 260 ml of water. At the end of the exposure, the precipitate is filtered off, washed on the filter with a solution of 0.38 g sodium hydroxide in 65 ml of water and a 0.25% solution of triethylamine in methanol.

Get 62.3 g of enol ether HELL (95%) with a mp of 171 ... 173 ^o C.

 Example 2

Растворяют при перемешивании 74 г гранулированного едкого натра в 34 мл воды и 1,3 л диметилсульфоксида при температуре 90-95^oC. После охлаждения до 60-65^oC к полученной суспензии прибавляют 100 г триметилсульфонийбромида, 6 г триэтилбензиламмонийхлорида (ТЭБАХ) и 130 г 3-метоксиандроста - 3,5 - диен - 17-она (енолэфира АД) и перемешивают в токе азота 4 ч при этой температуре. Реакционную смесь охлаждают до температуры 22 ± 4^oC, выливают в 2 л охлажденной до температуры +10^oC воды. Реакционную смесь охлаждают до (3 ± 2)^oC и дают выдержку при этой температуре в течение 1 ч. Осадок отфильтровывают, промывают 105 мл охлажденного до (3 ± 2)^oC метанола, сушат до постоянной массы. Получают 134,7 г (99% от теоретического) оксирана в виде кремового кристаллического порошка, т. пл. 128...131^oC, содержание исходного енолэфира АД не выше 2% (ТСХ-анализ).

With stirring, 74 g of granulated sodium hydroxide are dissolved in 34 ml of water and 1.3 l of dimethyl sulfoxide at a temperature of 90-95 ^o C. After cooling to 60-65 ^o C, 100 g of trimethyl sulfonium bromide, 6 g of triethylbenzylammonium chloride (TEBAX) and 130 are added to the resulting suspension. g of 3-methoxyandrost - 3,5 - diene - 17-one (enol ether) and stirred in a stream of nitrogen for 4 hours at this temperature. The reaction mixture is cooled to a temperature of 22 ± 4 ^o C, poured into 2 l of water cooled to a temperature of + 10 ^o C. The reaction mixture was cooled to (3 ± 2) ^° C and held at this temperature for 1 hour. The precipitate was filtered off, washed with 105 ml of methanol cooled to (3 ± 2) ^° C, and dried to constant weight. Get 134.7 g (99% of theoretical) of oxirane in the form of a creamy crystalline powder, so pl. 128 ... 131 ^o C, the content of the original enol ether BP is not higher than 2% (TLC analysis).

 Example 3

пропионовой кислоты (лактон).

propionic acid (lactone).

36 g of sodium metal are dissolved with stirring in 1.8 l of absolute ethanol and 238 ml (251 g) of malonic ester and 315 g of oxirane are added. The reaction mixture is boiled for 4.5 ... 6 hours. Ethanol is then distilled off at atmospheric pressure in an amount of 1.5 L, and 1.5 L of dimethyl sulfoxide and 350 ml of a 14.3% aqueous solution of sodium chloride are added to the residue. The reaction mass is heated to 100 ^o C and stirred for 3.5 ... 5 hours. Cooled to 35 ^o C the reaction mass is poured into 5.25 L of water and stirred for 20 minutes at this temperature. Then cooled to 5 ^o C and incubated for 2 hours. Precipitate: filtered off, washed with water to pH 7, dried. 351.3 g (98.2%) of lactone are obtained with a melting point of 219 ^o C.

 Example 4

пропионовой кислоты спиродиен).

propionic acid spirodien).

To a suspension of 62.5 g of lactone in 93.8 ml of acetone and 12.5 ml of water, 25 g of dibromantin or 28 g of N-bromosuccinimide are added portionwise with stirring. During the addition, the temperature rises to (28 ± 2) ^o C. The suspension first dissolves, and then a precipitate precipitates from the solution. Excerpt at this temperature for 20 minutes. Then, 187.6 ml of dimethylformamide and 7.5 g (5.3 g of 100%) lithium bromide and 6.8 g of lithium carbonate are added to the reaction mass and stirred at (79 ± 1) ^o C 3.5 ... 4 h After cooling to (20 ± 1) ^o C, the reaction mixture is filtered from inorganic salts, washed with 73 ml of dimethylformamide. The combined dimethylformamide solution of the obtained spirodiene is added dropwise over 25.. .30 min in 1100 ml of water, cooled to 3 ± 2 ^o C, and incubated for 30 min at this temperature. The precipitate is filtered off, washed with 160 ml of water to a neutral district. Dried at 40 ... 50 ^o C to constant weight. Obtain 54.5 g (60%, 43.6 g 100%, 95% of theory) of spirodiene in the form of a creamy crystalline powder, so pl. 140 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{2}}{\text{D}}$ ⁰ + 18 ^o E% 1 cm 800.

 Example 5

пропионовой кислоты (спиронолактон).

propionic acid (spironolactone).

20 g of technical spirodiene are dissolved in 70 ml of methanol with heating, 2 g of activated carbon are added and boiled for 30 minutes. The resulting solution was filtered from coal, washed with 40 ml of hot methanol. 8 ml of thioacetic acid is added to the filtered reaction solution, boiled for 3 hours with stirring in a stream of nitrogen. The reaction mass is cooled and incubated for 3 hours at -5. . .-10 ^o C. the Precipitate is filtered off and washed with 40 ml of chilled methanol.

16.64 g (85% of theory) of technical spironolactone are obtained in the form of a yellowish crystalline powder with a melting point of 185-192 ^o C. After purification from a mixture of acetone-menthol, the yield of spironolactone pharmacopoeial quality of 80% of theoretical, counting on spirodiene.

Example 6. Androst-4-en-3,17-dione (II, HELL, R ¹ and R ² together keto group)
The culture of Mycobacterium smegmatis VKPM Ac-1552 at 6 days old, grown on agar medium of the following composition (in g / l): glucose - 10, soy flour - 3, citric acid - 2.2, urea - 0.5, potassium dihydrogen phosphate - 0.5, ammonium chloride -1, magnesium sulfate - 0.5, iron sulfate - 0.05, agar-agar ~ 25, distilled water, pH before sterilization - 6.8-7.0, transferred to 30 ml of liquid seeding medium in conical flat-bottomed flasks with a capacity of 250 ml. The composition of the seed medium (g / l): glucose - 10, soy flour - 3, urea - 0.5, citric acid - 2.2, ammonium chloride -1, potassium dihydrogen phosphate - 0.5, iron sulfate - 0.05, magnesium sulfate - 0.5, calcium carbonate - 1.5, distilled water, pH before sterilization - 7.0. Incubated for 48 hours on a rocking chair with vigorous stirring 220 rpm (eccentricity 5 cm) and a temperature of 30 ^o C.

 The grown culture is added in an amount of 10 vol.% To the medium of the following composition (g / l): glucose - 10, soy flour - 10, urea - 0.5, ammonium hydrogen phosphate - 1.5, citric acid - 2.2, magnesium sulfate 0.2, iron sulfate 0.05, calcium carbonate 1.5, distilled water, pH before sterilization 7.0. The medium is poured into similar 30 ml flasks. Before sterilization, well-homogenized cholesterol is added to the medium in an amount of 1% (concentration 10 g / l). Fermentation is carried out on a rocking chair under the conditions described for obtaining vegetative inoculum for 96 ± 4 hours. At the end of fermentation (blood pressure - 7.0 g / l according to HPLC analysis), the culture fluid is separated from the biomass by centrifuge. The biomass is extracted with aqueous acetone (60-65% content).

The solvent was evaporated in vacuo to stop the run. From the resulting aqueous suspension, the technical target product is filtered. After recrystallization from methylene chloride and hexane, blood pressure is obtained with a yield of 70% and a melting point of 172-174 ^o C.

 Example 7

(II, циангидрин АД, R¹=CN, R²=OH)
К раствору 1,63 г NaOH в 280 мл метанола добавляют 100 г АД (II). Суспензию нагревают до 40^oC и добавляют последовательно 13,8 мл воды и 47,8 мл ацетонциангидрина. Реакционную массу выдерживают при температуре 35-36^oC в течение ч и добавляют медленно по каплям 59 мл воды, затем выдерживают при комнатной температуре. По окончании реакции добавляют медленно 217 мл воды и выдерживают 2 ч при комнатной температуре. Осадок отфильтровывают, промывают на фильтре смесью воды и метанола (2:1 соответственно) и водой до pH 7.

(II, cyanohydrin HELL, R ¹ = CN, R ² = OH)
To a solution of 1.63 g of NaOH in 280 ml of methanol was added 100 g of HELL (II). The suspension is heated to 40 ^° C. and 13.8 ml of water and 47.8 ml of acetone cyanohydrin are successively added. The reaction mass is maintained at a temperature of 35-36 ^° C. for one hour and 59 ml of water are slowly added dropwise, then it is kept at room temperature. At the end of the reaction, 217 ml of water is added slowly and incubated for 2 hours at room temperature. The precipitate is filtered off, washed on the filter with a mixture of water and methanol (2: 1, respectively) and water to a pH of 7.

Get 104.45 g of cyanohydrin HELL with a yield of 95.5%, with a melting point of 174-176 ^o C.

 Example 8

(IV, 3-пропиленкеталь циангидрина АД, R¹= CN, R²= OH и R⁵ и R⁶ вместе 2,2-диметил-1,3-диоксановый цикл)
Суспензию 104,45 г циангидрина АД (II) в 522 мл хлористого метилена охлаждают до температуры 0...-5^oC и в токе азота добавляют последовательно 105 мл триэтилового эфира oрто-муравьиной кислоты, 156,7 г неопентилгликоля и 15,67 г n- толуолсульфокислоты. Реакционную массу перемешивают в течение 8 ч. По окончании реакции медленно добавляют раствор 68,3 г гидрокарбоната натрия в 1,3 л воды. Суспензию охлаждают до температуры 0...+5^oC и выдерживают в течение ч. Остаток отфильтровывают, промывают водой до pH 7.

(IV, 3-propylene ketal cyanohydrin HELL, R ¹ = CN, R ² = OH and R ⁵ and R ⁶ together 2,2-dimethyl-1,3-dioxane cycle)
A suspension of 104.45 g of cyanhydrin AD (II) in 522 ml of methylene chloride is cooled to a temperature of 0 ...- 5 ^o C and 105 ml of ortho-formic acid triethyl ester, 156.7 g of neopentyl glycol and 15.67 are successively added in a stream of nitrogen g n-toluenesulfonic acid. The reaction mass is stirred for 8 hours. At the end of the reaction, a solution of 68.3 g of sodium bicarbonate in 1.3 l of water is slowly added. The suspension is cooled to a temperature of 0 ... + 5 ^o C and incubated for hours. The residue is filtered off, washed with water to pH 7.

Obtain 130.52 g of chromatographically pure 3-propylene ketal cyanohydrin AD with a yield of 98%, with a melting point of 252 ^o C (decomposition).

[α] $\genfrac{}{}{0ex}{}{\text{3}}{\text{D}}$ ⁵ = -22.5 ^° ± 4 ^° (c = 0.969 in chlorine).

Mass spectrum, m / z: 372 [M-HCN] ⁺ ; 286 [M-HCN-C ₅ H ₁₀ O] ⁺ .

IR spectrum, ν, cm ^-1 : 3396 (OH), 2252 (C≡N), 1672 (C = C), 1102, 1020 (-OCO-).

1 H-NMR spectrum, δ, ppm: 0.92 s and 0.96 s (3H 18-CH ₃ and 3H 19-CH ₃ ); 1.05 s (6H 2CH ₃ dioxane cycle); 3.55 m (4H 2CH ₂ -O dioxane cycle); 5.42 r.s. (1H 6-H).

 Example 9

(IV, 3-этиленкеталь циангидрина АД, R¹=CN, R²=OH и R⁵ и R⁶ вместе 1,2- диоксолановый цикл)
К суспензии 20 г циангидрина АД (II) в 20 мл этиленгликоля добавляют 40 мл 30% раствора метилортоформиата в метаноле и 0,4 г n-толуолсульфокислоты.

(IV, 3-ethylene ketal of cyanohydrin AD, R ¹ = CN, R ² = OH and R ⁵ and R ⁶ together 1,2-dioxolane cycle)
To a suspension of 20 g of cyanhydrin AD (II) in 20 ml of ethylene glycol, 40 ml of a 30% solution of methyl orthoformate in methanol and 0.4 g of n-toluenesulfonic acid are added.

The reaction mass is heated to 60 ^o C and stirred for 2 hours. At the end of the reaction, the reaction mass is cooled to 25 ^o C and add 0.6 ml of triethylamine (pH 8-9).

The reaction mass is cooled to a temperature of 0 ...- 5 ^o C and stirred for 2-3 hours. The precipitate is filtered off, washed on the filter with methanol, dried.

Get 19 g of 3-ethylene ketal cyanohydrin HELL with a yield of 83.6% and a melting point of 218-220 ^o C.

 Example 10

(V, 3-этиленкеталь оксирана, R⁵ и R⁶ вместе 1,2- диоксолановый цикл)
К смеси 7,2 г 3-этиленкеталя циангидрина АД и 6,8 г триметилсульфонийбромида в 145 мл диметилсульфоксида добавляют 7,2 г порошкообразного едкого натра. Суспензию перемешивают в течение 10 ч при температуре 60^oC. Затем к реакционной массе медленно добавляют 200 мл воды, массу охлаждают до комнатной температуры. Осадок отфильтровывают, промывают водой.

(V, 3-ethylene ketal oxirane, R ⁵ and R ⁶ together 1,2-dioxolane cycle)
7.2 g of powdered sodium hydroxide are added to a mixture of 7.2 g of 3-ethylene ketal cyanohydrin AD and 6.8 g of trimethylsulfonium bromide in 145 ml of dimethyl sulfoxide. The suspension is stirred for 10 hours at a temperature of 60 ^° C. Then, 200 ml of water are slowly added to the reaction mass, the mass is cooled to room temperature. The precipitate is filtered off, washed with water.

Obtain 6.52 g of 3-ethylene ketal oxirane with a yield of 94% and a melting point of 186-189 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{3}}{\text{D}}$ ⁵ = -60 ^° (c = 1 in hlf.).

1 H-NMR spectrum, δ, ppm CDCl ₃ : 0.94 s (3H, 18-CH ₃ ); 1.09 s (3H, 19-CH ₃ ); 2.78 s (2H, oxiranyl, CH ₂ ); 3.97 s (4H 2CH ₂ -O dioxolane ring); 5.4 m (1H vinylon, H).

 Further, the process is carried out similarly to examples 3-5.

Examples with enamine protection
Example 11. 3- (1-Pyrrolidinyl) -androsta-3,5-dien-17-one (II, R ⁵ and R ⁶ together pyrrolidine Deputy)
To a suspension of 10 g of HELL in 40 ml of methanol, heated to boiling point, slowly add 5 ml of pyrrolidine. At the end of the reaction, the reaction mass is cooled to a temperature of 0-5 ^o C. the Precipitate is filtered off, washed on the filter with chilled methanol. Obtain 10.7 g (90%) of pyrrolidine enamine HELL with a melting point of 217-220 ^o C.

Example 12. 3- (4-Morpholinyl) -androsta-3,5-dien-17-one (II, R ⁵ and R ⁶ together morpholine substituent)
To a suspension of 20 g of blood pressure in 120 ml of benzene add 50 ml of morpholine and 0.03 g of n-toluenesulfonic acid. The mixture is boiled, periodically removing the separated water. At the end of the reaction, the reaction mass is cooled to room temperature. The solvent was evaporated in vacuo to stop the run. To the residue add 10 ml of petroleum ether (fraction with a boiling point of 70-90 ^o C). The precipitate is filtered off, washed with petroleum ether.

Get 23.8 g (95.9%) of the morpholine enamine HELL with a melting point of 205-207 ^o C.

Sources of information
1. Enlinger E., Magnus PJAm. Chem. Soc., 1980, v. 102, 15, p. 5004-5011.

 2. Sturtz G., Yanakej J., Synthesis, 1980, 4, p. 289-291.

 3. Pat. US 3,738,983, 1974

 4. Pat. US 3682894, 1973

 5. Pat. US 4057542, 1977

 6. Japanese application 57-85400, 1978

 7. Japanese application 57-197300, 1978

 8. Pat. US 4,265,816, 1980

 9. Japanese application 61-359, 1981

 10. Pat. US 4,211,701, 1980

 11. Japanese application 53-124252, 1974

 12. Pat. FR 2216273, 2281357, 1974

Claims (9)

1. The method of obtaining

propionic acid of formula I

consisting in the fact that androstenedione or its derivative of the formula II

where R ¹ is carbonitrile, R ² is hydroxyl, the Δ ⁴ -3-ketosystem is protected, methyleneated at the 17-keto group with dialkylsulfoniummethylide, generated in situ from a trialkylsulfonium halide, with subsequent conversion of the obtained oxirane ring to a lactone one, by constructing an Δ ^4,6- dienone structure adding thioacetic acid and isolating the target product, characterized in that the construction of the dienone system is carried out after the construction of the lactone ring and simultaneous decarboalkoxylation by heating in an aprotic solution erator in the presence of catalytic amounts of a saturated aqueous solutions of salts of strong bases and strong acids and subsequent selective functionalization of the 6th position of the steroid molecule via halogenation reactions - dehydrohalogenation. 2. The method according to claim 1, characterized in that the androstenedione is obtained by microbiological oxidation of sterols of plant or animal origin of the general formula III

where R ³ is acyl or alkyl or carboxyacyl or H atom;
R ¹ is H or C ₂ H ₅ ,
and its derivative of formula II is obtained by the interaction of androstenedione with acetone cyanohydrin. 3. The method according to claim 1 or 2, characterized in that the protection of the Δ ⁴ -3-ketosystem of the androstenedione derivative of the formula II is carried out by forming spiroketals based on ethylene glycol, or 2-mono- or 2,2-disubstituted or unsubstituted derivatives 1,3 -propanediol, or pyrrolidine or morpholine enamines, or enol ethers.  4. The method according to any one of claims 1 to 3, characterized in that the generation of dialkylsulfoniummethylide in situ from trialkylsulfonium halide is carried out in the presence of a strong base.  5. The method according to claim 4, characterized in that tert-butylates or hydrides or hydrated alkali metal hydroxides are used as a strong base.  6. The method according to claim 4 or 5, characterized in that said generation is also carried out in the presence of a phase transfer catalyst.  7. The method according to claim 6, characterized in that the quaternary ammonium salts in an effective amount are used as a phase transfer catalyst.  8. The method according to claim 7, characterized in that trialkylarylammonium halides are used as the quaternary ammonium salt.  9. The method according to any one of claims 1 to 8, characterized in that in the halogenation reaction, dibromantin, or N-bromoacetamide, or N-bromosuccinimide is used as a halogenating agent, and dehydrohalogenation is carried out in an aprotic solvent using alkaline and alkaline salts land metals.