SU293345A1 - METHOD OF OBTAINING STEROID COMPOUNDS - Google Patents

Description

The invention relates to the field of production of steroid compounds.

A method is proposed for preparing compounds of the estratriene series of the general formula I not described in the literature.

OR,

4-CH, R,

where Ri represents a hydrogen atom or an acyl, tetrahydronyranyl, N-phenylcarbamoyl group, and Ro represents a rhodanide, azide, cyanide, mercapto, alkylmercanto, arylmercapto, acylglutocogrin, halogen atom, alkoksp, aryloxy, acyl, acetylcapto, acylgramtogrand, halogen atom, alloxid, aryloxy, acylgene, aryloxy, acylglobenyl and hydroxyl group.

The method consists in the fact that the 17p-spiro-I, 21-oxirane of the estratriene series of formula II

O-CH,

rhodium, hydrocyanic acid, hydrohalic acid, hydrogen sulfide, mercaptan, alcohol, primary or secondary amine, Boda, thnol acid, carboxylic acid or its salt, in an organic solvent, such as ether, dimethyl sulfoxide, ethylene glycol, etc., in the presence of a basic or acid type with the formation of compounds of the formula P1

-CH, R,

The compound obtained in this way is esterified to isolate the target product by the usual method by reacting a substance of formula P1 with an acid or its derivative, dehydroiurep or phenyl isocyanate.

Example 1. 3-Llotoxy-17a-rhodanomethyl-estra-1, 3.5 (10) -trien-17p-ol.

To a solution of 597 mg (0.002. "Olg) 3-methoxyestra-1, 3.5 (10) -trien-17 | 3-spiro-11,2-oxirane B, 30 ml of ether and add dropwise at room temperature and stirring an ethereal solution of hydrochloric acid, taken in excess. After 1 minute, the precipitate is precipitated. Reaction mixture

allowed to stand at room temperature for 24 hours. After this, the precipitate is aspirated ii and the 3-methoxy-7a-genus 1stystylester-1,3,5 (10) triple-17p-ol is thus washed with cold ether. Exit 645 mg (90%), so pl. 175-180 ° С, + 55 ° (С - 1, acetone).

Example 2. 3-Methoxy-7o: .- azidol ethylene-1, 3.5 (10) -triei-17r-ol.

To a solution of 1.19 g (0.004 mol) of 3-methoxyestr a-1,3,5 (10) -triene-17 5-spiro-I.21-oxyrap in 60 ml of dry dimethyl sulfoxide was added 3.0 g of azide and 10 drops of a co-degreased seric acid are added dropwise and, at a temperature of 10 min. In this case, the mixture is stirred and aggravates the reagiopia mixture for 2/2 hours and a boiling water bath. After the expiration of the VRS, 1eii, a full transformation of the epoxy groups occurs. After cooling, the reaction mass is poured on ice and the product is extracted with sulfuric ether. Ether solution is washed with water and a solution of sodium bicarbonate and immediately dried over sodium sulfate. After distilling off the sulfur eff. | Nra, a practically pure 3-methoxy-17cc azidometre 1astra-1,3,5 (10) -trien-17p-ol is obtained. After unspecified installation of an Isiron iron film, the product is obtained in the form of colorless ngl, water, and their temperature is 130–132 ° C; (C., acetone), the yield is 1.24 g (91%).

Example 3. 3-Methoxy-17a-cypaiometnlestra-1, 3.5 (10) -trisn-17p-ol.

To a solution of 1.49 g (0.005.) Of 3-methoxnestra-1, 3.5 (10) -triep-17 | 3-spiro-1,21-oxirane in 60 ml of ethylene glycol is added 3 g of 1) potassium chloride and heat the mixture for 2/2 hours in a water bath. After cooling, the reaction mass is poured onto water, a slightly yellow precipitated precipitate is sucked off and washed with water. The Pechisheipn product is dried in a desiccator over a phosphorus oxide and then recrystallized from a mixture of benzene-petroleum ether. Z-Metoxn-Po-, cyanomethnlaster-1, 3.5 (10) -trieno-17p-ol forms colorless needles with m. Pl. 144 to 147 ° C; c / Jg +58 (C .. 1, acetone), the yield was 1.57 g (96%).

Example 4. 3-Methoxy-17a-lurfolipol-1-ethyl estr-1,3,5 (10) -trien-17p-ol.

0.895 g (0.003 mol) of 3-methoxnestra-1,3,5 (10) -trien-17r-siro-11,21-oxirane is dissolved in 30 ml of 90% iz propylene sr; hrta and the resulting solution is mixed with 1 ml morpholine and 1 ml of 20% acetic acid. The reaction mixture is heated under reflux to KPenn and the process continues until the analysis of the reaction mixture by thin layer chromatography shows the presence of the initial components of the reaction in it. In this case, from 40 to 50 hours is required to complete the reaction. Immediately after this, the reaction mass is poured into water, the separated segregation

This is not a pure product and is washed thoroughly with water. After recrystallization of the crude product from methyl alcohol, the desired product is obtained in the form of colorless needle crystals; so nl 145-147 C; a g + 43 (, acetone).

The output of 1.07 g (94%).

Example 5. 3-Methoxy-17a-yetylaminomethyl-1, 3.5 (10) -trien-17p-ol.

0.10 g of 3-methoxy-estra-1,3,5 (10) -trien-17rsiiro-1, 2-oxnran is dissolved in 25 ml of ethanol and then 8 ml of 30% aqueous solution are added to the resulting jiacTBOpy.

methylamine and 2 ml of 20% acetic acid, the reaction mass is left to stand at room temperature for 8 days. On expiry of the specified time, a complete transformation of all epoxy groups occurs. The reaction mixture is taken up in water, the colorless crude product is filtered off with suction, washed thoroughly with water and, after drying, recrystallized from a mixture of acetone and sulfuric ether. 3-methoxy-17cc-methylamiomethylestra -1,3,5 (10) -trien17r-ol is obtained in the form of lamellar crystals, which have t. Nl. 90.5-93 ° C. The output was

Example 6. 3-Methoxy-17- (N-acetyl) -metlpal ipometplastra-1, 3.5- (10) -triene-17 | 3-ol.

0.62 g (0.002 mol Z-methoxy-Pa-metnlaminomethylnestra-1, 3.5 (10) -trien-17p-ol and susnent in 20 ml of absolute sulfur ether and the resulting suspension is mixed with 2 ml of anhydride acetic acid. 11). the mixture was incubated overnight at room temperature: 1, the reaction was then distilled and the ethyl ether was distilled off and the residue was distilled from methyl alcohol. As a result of the operations, 0.56 g (73%) of 3-methoxy} 7ci - (X - acetyl) - methylaminomethylether was obtained, 3.5 (10) -trien-17p-olas t. Nl. 180-18GS.

Pr and measures 7. 3-Methoxn-G7- (N-acetyl) -butplamipomethylestra-1, 3.5 (10) -triene-17p-ol.

0.89 g (0.003 lgol) 3-methoxyestra-1,3,5 (10) trnen-17 (3-spiro-1,2-oxpran) is dissolved in 30 ml of ethyl acetate and 3 ml of butylamine is added to the resulting solution, 1 ml

20% acetic acid and 4 ml of water. The reaction mixture is heated under reflux for 12 hours. After this time has elapsed, the reaction .L1aecu is poured into ice water, and the separated

at the same time the precipitate is washed with water. After drying, the obtained product is dissolved in diethyl ether and the solution is shifted with 2 ml of acetic anhydride. The mixture was allowed to stand overnight at room temperature. Diethyl ether is then evaporated. The residue after sterilization is distilled from methyl alcohol. The resulting compound is formed into colorless needles which have

Example 8. 3-Methox-17- (K-acetyl) -obenylaminomethyl 11 -stra-1, 3.5 (0) -tr1-cn-17 (3-ol /

0.89 g (0.003. Iol) 3-: 1etox-11esgra-1.3.5 (0) trien-17p-spiro-1, 2-oxyrapa is dissolved in 75 ml of ethyl alcohol and mixed with 7 ml of aniline and one drop acetic acid. The reaction mass iiarpe for 2 hours in a water bath and then immediately diluted with water: and evaporated to dryness in vacuum. The semi-solid residue is dissolved in 20 ml of diethyl ether and the solution is mixed with 2 ml of anhydride of acetic acid. After a short period of time, 3-methoxy-17- (N-acetnl) -phennlaminomethylestra-1, 3.5 (10) -trien-17p-ol begins to be released. The crystalline precipitate separated during the night in a hollow powder precipitate is sucked off and after washing with a small amount of diethyl ether, the colorless 1-methyl pure product from methyl alcohol is non-recrystallized. Get the product in the form of colorless needle crystals with t. Nl. 184-185 ° С Yield 0.70 g (557o).

Example 9. 3-Methoxy-17a-beisylaminomethyl-1, 3.5 (10) -tr yen-17p-ol.

0.89 g (0.003 l) of 3-methoxyestra-1,3,5 (10) triene-17 | 3-spiro-G, 2-oxirane is dissolved in 80 ml of ethyl alcohol and then 8 ml of benzylamine added to the resulting solution and one Kyle acetic to the slots heated the reaction mass for 20 hours under reflux. Directly after the ethnm, the solvent is distilled off, the residue after evaporation is repeatedly treated with water and the precipitate formed in this process is sucked off. After recrystallization of the crude product from the methyl sheet, 0.49 g (40%) of colorless needles, which have a melting point, are obtained. from 130 to 131 ° C.

Example 10. 3-Methoxy-17cc- (X-acetyl) benzylaminomethylestra — 1,3,5- (10) -triene17 (3-ol.

100 mg of 3-methoxy-17a-benzyl pto ietilera-1, 3.5 (10) -trien-17p-ol is dissolved in 10 ml of diethyl ether and the resulting solution is mixed with 1 ml of acetic anhydride. The crude acetate precipitated by the reaction is filtered off with suction and recrystallized from methyl alcohol. 55 mg (50%) of the product are obtained in the form of colorless needle crystals with m. Il. 202-204 ° C.

Example P. 3-Methoxy-17a-chloromethylethra-1, 3.5 (10) -trien-r-ol.

4.17 g (0.014 mol) of 3-methoxyestra-1,3,5 (10) trien-17p-spiro-1, 2-oxirane is dissolved in 70 ml of dimethylformamide and the resulting solution is mixed with a solution consisting of 7.5 ml of concentrated hydrochloric acid and 30 ml of dimethylformamide. After 20 minutes after mixing, the reaction mixture is poured into water, allowed to stand in this state for some time, and then the colorless precipitated during this time is sucked off

flaked product. After washing with a large amount of 1: esg1; ol of water and day crude, 10 sec;: s: allp,: obyvayu: from dpizoiroplivogo ether. 3.06 g of product are obtained in the form of colorless needle-like crystals with mp. 115-Fri. C. The yield is 65%.

PR and V. ep 12. 3-Mstoksn-7a-bromometiestra-1, 3.5 (10) -trie1 -17р-ol.

4.17 g (0.01 4-Voj; /) 3-: etoxyestra-1,3,5 (10) trisn-17p-crp1pro-1 .2-oxnran is dissolved in 70 ml. D. Methylformamide and the resulting solution of Quay with a solution consisting of 4.5 .iL7 of 48% hydrobromic acid and 30 mg of D1: methylformamide. After 20-30 minutes, a complete synthesis of the reaction components occurs. Immediately after this, the reaction mass is poured into water. The precipitated out at this: .1 the colorless chlorine-like crude product is sucked off, washed with water and recrystallized after dysopropyl ether. As a result of the operations performed, 3.82 g of product are obtained in the form of colorless plastic crystals; so nl 35-137C. Yield 71.5%.

Example 13. 3-.Metox-17cc-acetoxymethyl-1, 3.5 (10) -triey-17 | 3-ol.

0.89 g (0.003. Co.) Of 3-methoxy-estra-1,3,5 (10) Triep-17 | 3-spiro-1 .2-oxirane is heated in 10 .4.2 acetic acid for 4 hours on a knife water bath. After the indicated time has elapsed, the reaction mass is poured onto ice, and the colorless crude product which is separated out during this is extinguished and thoroughly washed with water. After drying, the crude product is recrystallized from hexane. As a result of the operations performed, 0.78 g of product is obtained in the form of fine needle-like crystals, which have a melting point of pl. 90-92 ° C. The yield is 72.5%.

Pr and measures 14. 3-Methox-17a-oxymethylester-l, 3.5 (10) -triene-17p-ol.

0.89 g (0.002 mol) of 3-methoxyestra-1,3,5 (10) triene-17 | 5-spnro-1, 2-oxirane is suspended in 10 ml of dioxane and after adding 1 ml of 1N to the suspension. caustic soda the reaction mixture is heated for 2 hours under reflux, and as a result of the reaction, the steroid goes into solution. After cooling, the reaction mixture is poured into water and the aqueous suspension is extracted with ether of the yKcyciiOii acid. After evaporation of the I5t of the washed and dried extract, a crystalline, crude product is obtained, which is then converted from methyl alcohol. Colorless needles are obtained with m. Pl. 168-171 ° C. The yield of products is 0.68 g (75.5%).

Example 15. 3-Methoxy-17a-methoxymetnlestra-1, 3.5 (10) -trnen-17p-ol.

0.89 g (0.003 .1.ol) 3-methoxy-estra-1,3,5 (10) trnen-17p-spiro-1, 2-oxirane is dissolved in 20 ml of absolute methyl sprint and after adding 10 ml to the batch solution 6n. sodium methoxide solution, the reaction mixture is heated for 3 hours under reflux. After this time has elapsed, the reaction mass is poured into water and the colorless crude product which is sucked off, which is then washed with water. After recrystallization of the crude product from methyl alcohol, a pure product is obtained in the form of fine needle-like crystals, which have a melting point of 200 ml. 109-110.5 ° C. Yield 0.78 g (78.5%).

Example 16. 3-Methyl ester-17p-acetoxy-17a-rhodanomethylester - 1,3,5 (10) -triene.

0.50 g of 3-methyl ester of 17p-hydroxy-17a-rhodanomethylestra-1, 3.5 (10) -triene is heated for 4 hours under reflux in 20 ml of dry benzene with 3 ml of acetic anhydride and 20 mg of P toluenesulfonic acid. After that, the reaction mass is cooled. The benzene solution is thoroughly washed with sodium hydrogen carbonate solution and water, and then dried over sodium sulfate. After evaporation of the solvent, a solid, colorless residue is formed, which is subjected to alumina chromatography. After elution with benzene, 0.28 g (50% of theoretical) of pure 17p-acetoxy-17a 3-methyl ester, -rodanomethylestr-1, 3.5 (10) -triene with m.p. 146-147 ° C.

Example 17. 3-Methyl ester of 17p-tetragndropyranyloxy - 17a - rhodanomethyl 1, 3.5 (10) -triene.

2.2 g of 17p-hydroxy-7a-rhodanomethyl-estra-1, 3.5 (10) -triene p-methyl ester is dissolved by heating in 150 ml of dry benzene. For complete dehydration of the reaction mass: about 50 ml of benzene is slowly distilled off. After cooling, 8 ml of dihydropyran and 200 mg of anhydrous d-toluenesulfonic acid are added to the solution. The reaction was allowed to stand at room temperature overnight. Then the solution of a slightly yellow color is thoroughly washed with a solution of sodium hydrogen carbonate and water, and benzene is distilled off from the benzene solution after drying. The resulting syrupy yellow liquid after evaporation is mixed with dynzonyl ether. As a result of crystallization, the product is sucked off. As a result of the conducted preparation, 0.9 g (37% of the theoretical) 3-methyl ester of 17p-tetrahydroiiraylox) of 1-17a-rhodiomethylene-1, 3.5 (10) -triene with m. Pl. 113-120 ° C. After recrystallization of the crude product from methyl alcohol, the sample analyzed is m.p. 127-127.5 p.

Example 18. The 17p-acetoxy-17a-azndometnl-estra 3-methyl ester - 1,3,5 (10) -triene.

1.02 g of 3-p-oxy-17a-azidomethylestra-1, 3,5 (10) -triene Z-methyl ester is heated for 3 hours under reflux in 30 ml of benzene with 5 ml of acetic anhydride in the presence of catalytic -toluenesulfonic acid. According to the indicated time, the reaction mass is washed with sodium carbonic acid solution and water and then the benzene solution is dried with sodium sulfate and the solvent is extracted. After recrystallization of the dark yellow residue obtained after sterilization, 0.52 g of methyl alcohol is isolated from methanol.

(45% of theory) 3-methyl ester

17p-acetoxy-17a-azidomethyl-estra-1,3,5 (10) triene, which has a melting point of pl. 114-115 ° C.

Example 19. 3-J ethyl ester 17p- (Nphenylcarbamoyloxn) -17a-azidomethylestra1, 3.5 (10) -triene.

1.02 g of 3-methyl-17p-hydroxy-17a-azidomethnlaster-1, 3.5 (10) -triene 3-methyl ester is dissolved in 20 ml of benzene and the resulting solution is added to a cooled 5 ml of phenyl isocyanate. The reaction mass is heated for 12 hours at the boiling point in a water bath and after the indicated time has elapsed, the solvent is removed. Balance after uirivani

subjected to chromatography on alumina. After elution with benzene, 0.80 g of a colorless product is obtained, which is recovered from methyl alcohol. As a result of irovedenny operations 0.62 g (45% of

theoretical) 3-methyl ester of 17p- (N-filylcarbo-yloxy) -17a-azidomethylestrate1, 3.5 (10) -triene, which has T. Il. 155,5-

157 ° C.

Example 20. 3-Methyl ester of 17p-acetoxy - 17a. - methoxymethyl ester - 1,3,5 (10) triene.

0.99 g of 3-methyl-17p-hydroxy-17a-methoxymethyl-estra-1, 3.5 (10) -triene 3-methyl ester is dissolved in 20 ml of benzene and, after the addition of 3 ml of acetic anhydride and 50 ml of d-toluenesulfonic acid to the solution, the mass is heated for 2 hours with a reversible refrigerator. Then the reaction mixture is cooled and the solution is:

sour carbonate and water. The benzene solution is dried over sodium sulfate and the solvent is stripped off. The colorless residue and after evaporation are recrystallized from methyl syirt. As a result of

operations, 0.82 g (73% of the theoretical) of 3-methyl ester of 17p-acetoxy-17metoxymethyl-1-3.5, 3.5 (10-triene with mp 121-1123 ° C., p and measures 21) are obtained. Methyl ester-17p- (Nphenylcarbamoyloxy) -17a. - methoxymethylestra-1, 3.5 (10) -trieium.

0.99 g of 3-methyl 17p-hydroxy-17a-methoxymethyl-estra-1, 3.5 (10) -triene 3-methyl ester is dissolved in 40 ml of benzene and after adding 2 ml of feiyl isocyanate to the base solution, the reaction mass is heated for 20 hours with reverse a fridge. Immediately after this, the solvent is distilled off in vacuo and the ocTaTOic formed is recrystallized from ethanol. Receive 0.70 g

(52% of theory) of 3-methyl ester

17p- (N-phenylcarbamoyloxy) -17-cc-methoxymethyl-estra-1, 3.5 (10) -trieium with t. Il. 130-135 ° C.

EXAMPLE 22. C-Methyl ether-17p-ace0, 20 g of 3-methyl ester of 17p-hydroxy-17a-cyanomethylestra-1, 3.5 (10) -triene is dissolved in 10 ml of absolute benzene and after adding to the resulting solution 1 ml of acetic anhydride and 0 mg of toluene sulfonic acid, the reaction mixture is heated for 2 hours under reflux. After cooling, the reaction mass is diluted with benzene, washed with sodium hydrogen carbonate solution and water, and dried over sodium sulfate. The residue formed after evaporation of the solvent is recrystallized from benzene-petroleum ether. As a result of the operations performed, 0.11 g (50% of theoretical) of 3-methyl ester17 (3-acetoxy-17a; -cyanomethyl 1, 3.5 (10) -triene with mp 139-141.5 ° C is obtained.

Subject invention

The method of producing steroid compounds of estratriene series of general formula I

OR, 4-CHjRj

wherein Ri represents a hydrogen atom or an acyl, tetrahydropyranyl, N-phenylcarbamoyl group, and R2 represents

rhodanide, azide, cyapid, mercapto, alkyl mercapto, aryl mercapto, acyl mercapto groups, halogen atom, alkoxy, aryloxy, acyloxy, a substituted amino group and its salt and hydroxyl group, characterized by the fact that 17p-spiro-11,2-1,2,2,21,21,21,21,21 is alkyloxy; estratriene series of the formula P

ten

treat nucleophilic m with a reagent, for example, hydrocyanic acid, hydrogen nitric acid, hydrocyanic acid, hydrohalic acid, hydrogen sulfide, mercaptan, alcohol, primary or secondary amine, water, thioacid, carboxylic acid or its salt, in the medium of an organic solvent in the presence of a catalyst of the basic or acid type with formation . m compounds of formula HI

HE

-gn, n,

111

30 which is esterified with the subsequent isolation of the target product in the usual way.