The method of obtaining-lactone 3(7-acetylthio-17-hydroxy-3 - oxoandrosta-4-en-17-yl)propionic acid

 

(57) Abstract:

The invention relates to pharmaceutical chemistry, and in particular to an improved method for producing a potassium-sparing diuretic such as spironolactone (verospiron, aldactone) of the available raw materials - Starinov of plant and animal origin. Via the described method spironolactone propionic acid] of the formula I

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derived from Androstenedione or its derivative of the formula II

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where R1- carbonitril, R2is hydroxyl, is subjected to protection4-3-closetime, metroidvania 17-ketogroup dialkylaminomethyl, generiruemyi in situ from trialkylphosphine, with subsequent conversion of the obtained oxiranes cycle in the lactone build4,6-Diakonova patterns, attach teoksessa acid and isolation of the target product. Building4,6-Diakonova system is carried out after the pre-build lactoovo ring and simultaneous descarboethoxyloratadine by heating in an aprotic solvent in the presence of catalytic amounts of saturated aqueous solutions of salts of strong bases and strong acids, selective functionalization of 6-th position erased the slot and produce the target product. The method allows to increase the yield of the main product by avoiding the formation of by-products and resinification of the reaction mixture by carrying out reactions under mild conditions. 8 C.p. f-crystals.

The invention relates to the field of chemistry, and in particular to methods of obtaining potassium-sparing diuretic such as spironolactone (verospiron, aldactone) of the available raw materials - sterols of plant and animal origin.

Spironolactone [ propionic acid] of the formula (I).

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is a highly effective diuretic that has a number of advantages in comparison with other diuretics: does not change the structure of the renal epithelium, not characterized diabetogenic effect, can be used with hypokalemia caused by other diuretics.

Ways to get spironolactone (I) provide varieties of acetylene synthesis and further metallation etinilnoy group and its carboxylation with advanced protection hydrogenation of the triple bond, lactonization and building structure. The outputs of the individual stages high and are 88-95% [1-11].

In the known methods it is necessary to use at different stages of the synthesis of the two protective groups: atimeline drawback of these methods is the large-scale use of acetylene, use as metalliser agent sodium hydride, utility, Grignard reagent, and the use of on-stage hydrogenation of palladium catalyst or the application of pressure in the case of Nickel-boride catalyst, which complicates the process.

Another way to build molecules of spironolactone is based on the use of 17-spirooxazines.

The closest to the invention is a method of receiving spironolactone General formula (I), namely, that Androstenedione (AD) formula

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put the protection medienraum 17-ketogroup dialkylaminomethyl, generiruemyi in situ from trimethylsulfonium with the subsequent construction of the structure, the transformation obtained oxiranes cycle in lackenby, attach teoksessa acid and isolation of the target product [12].

In the known method descarboethoxyloratadine is at the last stage, and ester group in the lactone ring, going through several stages, can be either hydrolyzed to form a by-product, reducing the yield of the main product. In addition, the reaction descarboethoxyloratadine held in harsh conditions: high temperature and pressure in the presence of the main product by avoiding the formation of by-products and resinification of the reaction mass, carrying out reactions under milder conditions.

The technical result is achieved in that in a method of producing propionic acid of the formula (I)

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namely, that Androstenedione or its derivative of the formula (II)

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where R1- carbonitril, R2is hydroxyl, is subjected to protection4-3-closetime, metroidvania 17 - ketogroup dialkylaminomethyl, generiruemyi in situ from trialkylphosphine with subsequent conversion of the obtained oxiranes cycle in the lactone, the build system, attach teoksessa acid and isolation of the target product, the build system is carried out after the build lactone ring and simultaneous descarboethoxyloratadine 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 6-th position of the steroid molecule with the reactions of haloiding - dehydrohalogenating.

Moreover, Androstenedione (AD) is obtained by microbiological oxidation of sterols of plant or animal origin General formula (III)

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where R3- atilov (II) with R1- carbonitril, a R2- hydroxyl is produced by the interaction of AD with acetonecyanohydrin.

In addition, the protection derived Androstenedione formula (II) can be done through education spirochaetales based on ethylene glycol, or 2 - mono -, or 2,2 - disubstituted or unsubstituted derivatives of 1,3 - propane diol, or pyrrolidinone or Martinovich of enamines or telefonov.

In addition, the generation of dialkylaminomethyl in situ from trialkylphosphine carried out in the presence of a strong base.

And as a strong base, using tert-butylate or hydrides, or hydrated hydroxide of alkali metals.

In addition, the generation can be performed also in the presence of phase transfer catalyst transfer.

In addition, as the phase transfer catalyst of transition to use of the Quaternary ammonium salt in an effective amount.

As the Quaternary ammonium salt can be used trialkylaluminium.

In addition, in the reaction of haloiding as an agent, you can use diplomanden or N - or N-bromosuccinimide, and dehydrohalogenating Prov is about getting propionic acid (spironolactone) of the formula (I) is carried out according to the following scheme:

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where R5and R6- isolater or cyclic ketal, or enamine.

Androstenedione (AD), is obtained by microbiological oxidation of sterols of plant or animal origin General formula (III) or its derivative (II) obtained by reacting the HELL with acetonecyanohydrin initially subjected to protection by 3 - ketogroup education telefonov, or cyclic ketals or enamines (compound of General formula (IV). Then this connection medienraum 17-ketogroup action dialkylaminomethyl, generated in situ from trialkyl-sulfonylated in the presence of a strong base and phase transfer catalyst transfer (or not) in an aprotic solvent.

Obtained with a yield of 99% oxiran (V) is converted into spirolactone (VII) condensation with diallylmalonate in the presence of sodium alcoholate followed by descarboethoxyloratadine 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. Selective functionalization of 6-th position is carried out using sequence lsout reagents allyl, synthesized, such as N-bromosuccinimide or N - bromoacetamide, or diplomanden in an aprotic solvent. The reaction dehydrobrominated carried out without isolating the intermediate product (VIII) in the presence of salts of alkaline or alkaline-earth metals at a temperature of 60-80oC. Formed with an exit 95% spiration (IX) is subjected to interaction with teoksessa acid. The total yield of spironolactone (I) corresponding to the requirement of the Pharmacopoeia, is 45 - 50%, counting on sterols (III), or 70.2 per cent, counting on derivatives AD (II).

The invention is illustrated by the following examples,

Example 1. Enlever HELL (3 - methoxyindol-3,5 - Dien-17-one).

To a solution of 19 g of triethylorthoformate in 146 ml of methanol add 62,5 g HELL. The suspension is stirred for 15 minutes and add slowly 142 ml of a solution of 0.125 g of sulfosalicylic acid in 26,74% solution of triethylorthoformate in methanol. The reaction mass is maintained at a temperature of 20...25oC for 1 h 15 min after exposure of the reaction mass is cooled to 10. . . 15oC, slowly add 46,9 ml acetone and incubated for 1 h at the same temperature. Then add 0.5 ml of triethylamine to pH 7-8, cooled the reaction mass to 0...+2oC and add a solution of 1.52 g is Drago of hydroxide in 65 ml of water and 0.25% solution of triethylamine in methanol.

Get 62,3 g Talavera HELL (95%) with T. pl. 171...173oC.

Example 2.

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Dissolved under stirring 74 g of granulated caustic soda in 34 ml of water and 1.3 l of dimethyl sulfoxide at a temperature of 90-95oC. After cooling down to 60-65oC to the resulting suspension was added 100 g of trimethylsulfonium, 6 g of triethylmethylammonium (TEBAH) and 130 g of 3-methoxyindole - 3,5 - Dien - 17-she (Talavera HELL) and stirred in a stream of nitrogen for 4 h at this temperature. The reaction mixture is cooled to a temperature of 22 4oC, poured into 2 liters of chilled to a temperature of +10oC water. The reaction mixture is cooled to (3 2)oC and give exposure at this temperature for 1 hour the Precipitate is filtered off, washed with 105 ml) cooled to (3 2)oC methanol, dried to constant weight. Get 134,7 g (99% of theoretical) of oxirane in the form of white crystalline powder, so pl. 128...131oC, the contents of the source Talavera HELL no higher than 2% (TLC analysis).

Example 3.

propionic acid (lactone).

36 g of metallic sodium are dissolved with stirring in 1.8 l of absolute ethanol and added 238 ml (251 g) of malonic ester and 315 g of oxirane. The reaction mixture is boiled for 4.5 foxed and 350 ml of 14.3% aqueous solution of sodium chloride. The reaction mass is heated to 100oC and stirred for 3.5...5 hours Cooled to 35oC the reaction was poured into a 5.25 l of water and stirred for 20 min at this temperature. Then cooled to 5oC and incubated for 2 hours the Precipitate: filtered off, washed with water to pH 7, dried. Get to 351.3 g (98.2 per cent) of the lactone with so pl. 219oC.

Example 4.

propionic acid spiration).

To a suspension of 62.5 g of the lactone in 93,8 ml of acetone and 12.5 ml of water in portions with stirring was added 25 g of dibromoethane or 28 g of N - bromosuccinimide. During the addition the temperature rises to (28 2)oC. the Suspension is first dissolved and then from solution precipitation. Give exposure at this temperature for 20 minutes Then the reaction mass is added 187,6 ml of dimethylformamide and 7.5 g (5.3g 100%) of methyl lithium and 6.8 g of lithium carbonate and stirred at (79 1)oC 3.5...4 hours After cooling to (20 1)oC the reaction mixture was filtered from inorganic salts, washed with 73 ml of dimethylformamide. United dimethylformamide solution obtained Spirogyra was added dropwise over 25. . .30 min in 1100 ml of water, cooled to 3 2oC, and incubated for 30 min at this temperature. The precipitate is filtered off, washed with 160 ml of water until the who) Spirogyra in the form of white crystalline powder, so pl. 140oC []2D0+ 18oE %1 cm 800.

Example 5.

propionic acid (spironolactone).

20 g of technical Spirogyra dissolved in 70 ml of methanol while heating, add 2 g of activated charcoal and boil for 30 minutes the resulting solution is filtered from coal, washed with 40 ml of hot methanol. To the filtered reaction solution was added 8 ml teoksessa acid, boiled for 3 hours under stirring in a stream of nitrogen. The reaction mass is then cooled and incubated for 3 h at -5. . .-10oC. the Precipitate is filtered off and washed with 40 ml of chilled methanol.

Get 16,64 g (85% of theoretical) technical spironolactone in the form of a yellow crystalline powder with so pl. 185-192oC. After purification from a mixture of acetone-methanol output spironolactone pharmacopoeial quality 80% of theoretical, considering spiration.

Example 6. Androst-4-ene-3,17-dione(II, AD, R1and R2together ketogroup)

Culture of Mycobacterium smegmatis PMBC Ac-1552 6 days of age, grown on agar medium of the following composition (in g/l): glucose - 10, soy flour - 3, citric acid - 2,2, urea and 0.5, potassium dihydrophosphate - 0,5, ammonium chloride -1, magnesium sulfate is 0.5, ferric sulfate, 0.05, the agar-AG is codenie flask with a capacity of 250 ml The composition of the seed medium (g/l): glucose - 10, soy flour - 3, urea and 0.5, citric acid - 2,2, ammonium chloride -1, potassium dihydrophosphate - 0,5, ferric sulfate, 0.05, the magnesium sulfate is 0.5, calcium carbonate and 1.5, distilled water, pH before sterilization - of 7.0. Incubated for 48 h on a rocking chair with vigorous stirring at 220 rpm (eccentricity 5 cm) and a temperature of 30oC.

Grown culture make in the amount of 10 vol.% on Wednesday of the following composition (g/l): glucose - 10, soy flour - 10, urea and 0.5, phosphate ammonium - 1,5, citric acid - 2,2, magnesium sulfate and 0.2, ferric sulfate, 0.05, the calcium carbonate - 1,5, distilled water, pH before sterilization - of 7.0. The environment is divided up in a similar flask and 30 ml prior To sterilization the medium was added well-homogenized cholesterol in the amount of 1% (concentration 10 g/l). The fermentation is carried out at the rocking chair in the conditions prescribed for obtaining vegetative inoculum during 964 hours At the end of fermentation, the concentration of AD - 7.0 g/l according to HPLC analysis) culture fluid is separated from the biomass in the centrifuge. Biomass is extracted with aqueous acetone (60-65% of the content).

The solvent is evaporated in vacuum until the termination of a shoulder strap. The resulting aqueous suspension otfit is with the release of 70% and a melting point 172-174oC.

Example 7.

(II, cyanhydrin HELL, R1=CN, R2=OH)

To a solution of 1.63 g of NaOH in 280 ml of methanol was added 100 g AD (II). The suspension is heated to 40oC and add sequentially to 13.8 ml of water, and 47.8 ml acetonecyanohydrin. The reaction mass is maintained at a temperature of 35-36oC for h and slowly add (dropwise) 59 ml of water, then incubated at room temperature. Upon completion of the reaction, add slowly 217 ml of water and incubated for 2 h 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 pH 7.

Get 104,45 g cyanhydrin HELL with access to 95.5%, with a melting point 174-176oC.

Example 8.

(IV, 3-propranolol of cyanhydrin HELL, R1= CN, R2= OH and R5and R6together 2,2-dimethyl-1,3-dioxane cycle)

Suspension 104,45 g cyanhydrin AD (II) in 522 ml of methylene chloride cooled to a temperature of 0...-5oC in a stream of nitrogen consistently add 105 ml teeterboro ether of ortho-formic acid, 156,7 g of neopentyl glycol and 15,67 g n - toluenesulfonic acid. The reaction mass is stirred for 8 hours At the end of the reaction slowly add a solution of 68.3 g of bicarbonate netvault, washed with water to pH 7.

Get 130,52 g of chromatographically pure 3-propylenes of cyanhydrin HELL with the release of 98%, melting point 252oC (decomposition).

[]3D5= -22,54(C=0,969 in chlf.).

Mass spectrum, m/z: 372 [M-HCN]+; 286 [M-HCN-C5H10O]+.

IR spectrum , cm-1: 3396 (OH), 2252 (CN), 1672 (C=C), 1102, 1020 (-O-C-O-).

PMR-spectrum , M. D.: 0,92 with and 0.96 (3H 18-CH3and 3H 19-CH3); of 1.05 (6H 2CH3dioxane cycle); 3.55 (4H 2CH2-O dioxane cycle); 5,42 ush.with. (1H, 6-H).

Example 9.

(IV, 3-atlantal of cyanhydrin HELL, R1=CN, R2=OH and R5and R6together 1,2 - dioxolane cycle)

To a suspension of 20 g of cyanhydrin AD (II) in 20 ml of ethylene glycol added 40 ml of 30% solution of meteorophobia in methanol and 0.4 g of n-toluenesulfonic acid.

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

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

Obtain 19 g of 3-atelectasia cetal of oxirane, R5and R6together 1,2 - dioxolane cycle)

To a mixture of 7.2 g of 3-atelectasia of cyanhydrin HELL and 6.8 g of trimethylsulfonium in 145 ml of dimethyl sulfoxide added 7.2 g of powdered sodium hydroxide. The suspension is stirred for 10 hours at a temperature of 60oC. Then, to the reaction mass slowly add 200 ml of water, the mass is cooled to room temperature. The precipitate is filtered off, washed with water.

Get 6,52 g 3-atelectasia of oxirane with the release of 94% and a melting point 186-189oC.

[]3D5= -60(C=1 in chlf.).

PMR-spectrum , M. D. CDCl3: to 0.94 (3H, 18-CH3); of 1.09 (3H, 19-CH3); 2,78 (2H, oxiranyl, CH2); of 3.97 (4H 2CH2-Dioxolane O cycle); 5.4 m (1H vinylon, N).

The process is conducted similarly to examples 3-5.

Examples enamines protection

Example 11. 3-(1-Pyrrolidinyl)-androsta-3,5-Dien-17-one (II,5and R6together pyrolidine Deputy)

To a suspension of 10 g of HELL in 40 ml of methanol, heated to boiling point, add slowly 5 ml of pyrrolidine. Upon completion of the reaction the reaction mass is then cooled to a temperature of 0-5oC. the Precipitate is filtered off, washed on the filter with cold methanol. holiner)-androsta-3,5-Dien-17-one (II, R5and R6together moholynagy Deputy)

To a suspension of 20 g of HELL in 120 ml of benzene are added 50 ml of research and 0.03 g of n-toluenesulfonic acid. The mixture is boiled, periodically removing the separated water. Upon completion of the reaction the reaction mass is then cooled to room temperature. The solvent is evaporated in vacuum until the termination of a shoulder strap. To the residue add 10 ml of petroleum ether (fraction with a boiling point of 70-90oC). The precipitate is filtered off, washed with petroleum ether.

Get to 23.8 g (95.9 per cent) morpholinothio of enamine HELL with a melting point 205-207oC.

Sources of information

1. Enlinger E., Magnus P. J. Am.Chem.Soc., 1980, v.102, 15, p.5004-5011.

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

3. Pat. US 3738983, 1974

4. Pat. US 3682894, 1973

5. Pat. US 4057542, 1977

6. Japan's bid 57-85400, 1978

7. Japan's bid 57-197300, 1978

8. Pat. US 4265816, 1980

9. Japan's bid 61-359, 1981

10. Pat. US 4211701, 1980

11. Japan's bid 53-124252, 1974

12. Pat. FR 2216273, 2281357, 1974

1. The method of obtaining propionic acid of the formula I

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namely, that Androstenedione or its derivative of the formula II

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where R1- carbonitridation, generated in situ from trialkylphosphine, with subsequent conversion of the obtained oxiranes cycle in the lactone, build4,6-Diakonova patterns, attach teoksessa acid and isolation of the target product, characterized in that building Diakonova system is carried out after the build lactone ring and simultaneous descarboethoxyloratadine 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 6-th position of the steroid molecule with the reactions of haloiding - dehydrohalogenating.

2. The method according to p. 1, characterized in that Androstenedione is produced by microbiological oxidation of sterols of plant or animal origin General formula III

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where R3- acyl, or alkyl, or carboxyethyl, or atom N;

R1- N or C2H5,

and its derivative of the formula II are obtained by interaction of Androstenedione with acetonecyanohydrin.

3. The method according to p. 1 or 2, characterized in that the protection4-3-closetime derived Androstenedione formula II implementation, the derivatives of 1,3-propane diol, or pyrrolidinone or Martinovich of enamines, or telefonov.

4. The method according to any of paragraphs.1 to 3, characterized in that the generating dialkylaminomethyl in situ from trialkylphosphine carried out in the presence of a strong base.

5. The method according to p. 4, characterized in that as a strong Foundation using tert-butylate, or hydrides, or hydrated hydroxide of alkali metals.

6. The method according to p. 4 or 5, characterized in that the specified generation is carried out in the presence of phase transfer catalyst transfer.

7. The method according to p. 6, characterized in that the phase transfer catalyst transfer use of the Quaternary ammonium salt in an effective amount.

8. The method according to p. 7, characterized in that the Quaternary ammonium salt used trialkylaluminium.

9. The method according to any of paragraphs.1 to 8, characterized in that in the reaction of haloiding as halogenous agent use diplomaten, or N-bromoacetamide, or N-bromosuccinimide, and dehydrohalogenating carried out in the environment aprotic solvent using salts of alkaline and alkaline-earth metals.

 

Same patents:

The invention relates to new derivatives of 17,20-epoxides Pregnana, to a method for their production and to their use as intermediates in the synthesis of biologically active products, specifically to derived 17,20-epoxides of General formula I

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where R-=0,-OH, and In the remains of

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and K=O, or group

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or

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where n=2,3;

R1-the remainder of the ether or of ester,

wavy lines indicate the mixture of isomers

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SUBSTANCE: invention relates to a method of producing ulipristal acetate which includes the following stages:

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8 cl, 22 ex

FIELD: chemistry.

SUBSTANCE: improved method of producing a known compound of the androstane series, 17,17-ethylenedioxy-androsta-1,4-dien-3-one is proposed. The process is carried out by reacting androsta-1,4-diene-3,17-dione with ethylene glycol in a heterogeneous medium in the presence of trialkyl orthoformate and arylsulfonic acid, followed by isolation of the desired product by filtration directly from the previously neutralized reaction mass.

EFFECT: new improved method is developed.

2 cl, 1 tbl

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