SU927117A3 - Process for producing derivatives of hexahydrobenzopyranoxanthogenones - Google Patents

Description

39 includes alkali metal salts, quaternary ammonium salts with a carbon content in the cationic residue 10-28, or a tertiary amine salt with a carbon content in the cationic residue 7-21.  The starting dihydrobenzyl pyrastanostenones of formula 2 are obtained by the interaction of alkoxy-substituted 2-hydroxybenzaldehyde with, -dimethyl-2,5 Cyclohexadiene in the presence of pyrrolidine or its mono- or di-substituted derivatives in an inert organic solvent at 0-B5 ° C.  Electrolytic reduction is carried out by dissolving or suspending the corresponding dihydrate.  Robenzipyranoxantenone in the medium of an organic solvent or in the environment, which is a water-organic mixture.  As an organic: solvent, amide type solvents are used, for example, M, M-dimethylformamide and H, H-dimethylacetamide, nitriles, such as, for example, acetonitrile, alcohols, for example, methanol and ethanol, aromatic hydrocarbons, such as benzene and toluene, halogenated hydrocarbons, such as methylene chloride and chloroform, etc. d.  Amides, nitriles or alcohols, such as N, N-dimethylformamide, acetonitrile or methanol are preferably used in the process.  o In particular, various salts are used as electrolytes, including halides, tosylates, and perchlorates of such alkali metals as lithium, sodium, and potassium or quaternary ammonium salts, such as, for example, halides and perchlorates of quaternary ammonium bases, such as tetraalkyl ammonium, trialkyl alkylammonium dialkyldiaralkylammonium or alkyltriaralkylammonium.  Preferably, tetrabutylammonium salt is used.  Another class of electrolytes are salts of tertiary amines and, in particular, halohydrates, tosylates and perchlorates of trialkylamines, dialkyl aralkylamines, alkylalkylamino amines and triaralkylamines containing in the cationic part in general from 7 DR 21 carbon atoms.  Tributylamine salts and, in particular, p-toluenesulfonate (tosylate) tributylamine are preferably used.  7 A proton source is also introduced into the reaction medium.  The best results are obtained with the use of relatively weak carboxylic acids having pKa ranging from 2 to 6, and, in particular, benzoic acid and acetic acid.  In the electrolytic reduction of dihydrobenzpyranoxantenone, it is present in the reaction medium in an amount of from about 1 to 15 mg per ml of medium.  The electrolyte is used in an amount of 0.01 mol-1.0 mol, and carboxylic acid in the amount of 1-5% by weight based on the volume of the reaction medium.  The mixture thus obtained is brought into contact with an electrolytic cathode. cells ; A potential corresponding to a background discharge point is applied to the electrodes of this cell.  This potential is determined by constructing a current-potential (current-voltage) curve for the working electrodes in the medium used before electrolysis.  Electrolytic cells consist of a suitably selected cathode and an anode separated by a bridge.  The cathode used in this process is usually mercury.  Materials that can be used to make the anode include platinum and carbon (graphite).  Metallic platinum is the most preferred material for the manufacture of the anode, especially when it is shaped into a thin metal mesh or wire cloth.  Carbon, due to its low cost, is another preferred anode material.  A bridge connecting the cathode and the anode may be a common salt bridge, such as, for example, A-percent (s aqueous mixture saturated with potassium chloride.  Such a bridge can also be a suitable porous membrane, for example an ion exchange membrane, a ceramic membrane or a membrane sintered from glass chips, whose porosity can vary from small to medium porosity.  The electrolytic cell consists of a glass cylindrical cathode compartment equipped with a thermostating jacket, in which a glass anodic compartment is hung, one of the elements of which is a porous glass plate sintered from powdered glass.  The cathode is present in the cell in the form of a mercury reservoir having an annular shape.  The anode compartment is usually a porous glass cylinder or a double-wall annular glass tube provided with an annular glass porous plate made of sintered glass powder and sunken into the bottom of said glass. This tube.  The anode is typically a platinum wire, dipped into the same mixture of organic or aqueous-organic medium and electrolyte, which is used to fill the cathode compartment.  The electrolysis cell is closed at the top with a cap, through which a deaerating plate (air filter), a reference probe electrode and a thermometer are inserted into the cell.  The reference probe electrode is a glass tube containing a fibrous pad into which a saturated calomel electrode is inserted.  The electrolytic reduction of dihydrobenzpyranoxantenone is carried out as follows: an appropriately selected mixture consisting of an organic or aqueous-organic medium, an electrolyte and a proton donor is placed in the cathode space of the electrolytic cell.  A pre-calculated amount (about 1-15 milligrams / ml) of the corresponding dihydrobenzpyranoxantenone is added to this mixture with stirring and then an annular anodic compartment containing a mixture of organic or aqueous-organic medium and electrolyte above the cathode is placed along with the cap ) covering the electrolytic cell. .  Then, a stream of argon is fed into the cell through a deaerating frit, which is passed through a stirred dMecb cathode.  After de-aeration has been completed (air is forced out with argon), which usually takes about 15 minutes, the deaerating fritte bubbler is lifted and fixed in a position above the surface of the solution in the cathode compartment, continuing to subsequently pass an argon current through the cell above the liquid.  Then to the cell electrodes. a predetermined electric potential is applied and maintained until the amount of current passed through the cell approximately corresponds to twice the Farad number required for the four-electron recovery.  The counting of the amount of electricity (in the pendants) passed through the system can be PRODUCED using a coulometer, and the process in the system can also be monitored using thin layer chromatography or high pressure liquid chromatography.  Any of these methods are useful for determining the degree of completeness of the reduction reaction.  After electrolysis is complete, the cathode solution is collected and processed to isolate the desired reaction product.  The treatment of the reaction mixture is carried out by the following methods: first, the majority of the organic or organic solvent is removed, the evaporation of the reaction mixture under vacuum is used.  The resulting evaporation syrup is dissolved in ethyl acetate.  The ethyl acetate solution is washed several times, usually with equal volumes of water, in order to remove the electrolyte and the proton donor.  The ethyl acetate phase is then dried over a suitable drying agent, such as, for example, anhydrous magnesium sulphate, and filtered to remove the solvent.  The dried ethyl acetate solution is evaporated in vacuo to remove the solvent, and the residue is dried for several hours in a vacuum oven at 5 ° C.  To obtain the desired hexahydrobenzpyranoxantenone, the resulting residue is recrystallized from a suitable solvent or solvent system.  The nature of the cationic electrolyte is extremely large. value for successful electrolytic reduction reaction.  The stereoconfiguration of the hexahydrobenzpyranoxantenone of formula 1 has been found to depend to a large extent on the specific electrolyte used for the process.   79 In the case when the electrolyte is a salt, the cation of which forms a strongly associated ionic pair (such cations include lithium, sodium or potassium cations) as a result of electrolytic reduction, a product is obtained, mainly consisting of hexahydrobenzpyranoxanthion having 5aj. . -, ba ,, and 13a | configuration.  In contrast, an electrolyte having a cation that forms a weakly associated ion pair (for example, a quaternary ammonium salt or a tertiary amine salt) corrects the electrolytic reduction in such a way that a product is obtained, predominantly consisting of hexahydrobenzpyranoxantenone, having 5aJv-, 6aL -, IZaJc-, and 13a b configuration.  Since in most cases (L, K, Jj-HSOMep is a more active anti-androgenic substance than the corresponding Jv /, A, p, is an isomer, it is most preferable to use the salt of the vertical ammonium salt as an electrolyte during electrolytic reduction of dihydrobenzpyranoxantenone base or tertiary amine salt g Example 1.  Receipt (Sai, ba. . ,) -6,6a-dihydro-6,6-dimethyl-5aH, 13H- / 1 / -benzpyra-yo (3,2-b) xanthen-13-it.  A solution of 30 g (0.25 mol) of salicylic aldehyde in 150 milliliters of benzene is cooled under nitrogen (after it is treated. first, 26.25 g of 0.37 mol of pyrrolidine) and then 15 ml (0.25 mol) of acetic acid are added to it with stirring.  After 15 minutes, the resulting mixture was added at room temperature to 15 g (0.125.  mole) 4, A-dimethyl-2,5-cyclohexadienone and the reaction mixture is heated with bOS overnight.  After cooling, the mixture is poured. in a large amount of ice water.  Organic  the layer is separated and washed twice in a separatory funnel with a 1% aqueous solution of acetic acid, and then three times with a 1 M solution of sodium hydroxide.  After final washing of the organic phase-saturated with a solution of sodium chloride, the organic solution is dried over anhydrous sodium sulfate.  The solvent 78 is then removed and the product obtained in the residue is recrystallized from benzene-hexane.  The yield after two recrystallizations is 18.6 grams (kf) 4 (theoretically possible).  The resulting target product has t. square  211-213 C and identified according to elemental analysis, IR-UV-and NMR-spectroscopy.  Elemental analysis: Found: C 79.76; H 5, b9.  C 22 H, 8 O J.  Calculated,%: C 79.98; H 5.9 Example 2.  Preparation of, 6a-dihydro-2,10-dimethoxy-6,6-dimethyl-5zN, 13H- /. 1 / -benzpirano (3,2-b) xanten-13 she.  A solution of 12.5 g (82 mmol) of 5 methoxysalicylic aldehyde in 100 ml of benzene is cooled under nitrogen after the addition of 8.73 g (123 mmol) of pyrrolidine and t, 92 grams (82 mmol) of acetic acid is added to it.  After the mixture was stirred at room temperature for several minutes, 5.0-g () 4, -dimethyl-2.5 cyclohexadiens was added to it, then the reaction mixture was heated under nitrogen at 60 ° C overnight, after which the mixture was cooled and poured into.  large amount of ice water.  The organic layer thus obtained is separated in a separatory funnel and washed successively with dilute acetic acid, a slightly dilute solution of sodium hydroxide and a saturated solution of sodium chloride.  The organic layer is then dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The residue is recrystallized twice from a mixture of benzene and, hexane.  In the end, get g (23) of the target product, having m square  219-220 C.  Elemental microanalysis: Found: C: 73.95, and 5.38.  WITH. .  Calculated: C 73.83, H 5.68.  Example 3  Receiving (5aJ-6aA. ) -6,6a-dihydro-3, 9 Dimethoxy-6,6-dimethyl-5aH, 1ZN- / 1 / -benzpyrno (3,2-6) xanthen-13 it.  A solution, I, 35 g (9 ", 4 mmol) of 4-methoxy aryl-aldehyde aldehyde in 100 ml of benzene was prepared. This solution is cooled and 10 g (Y mmol) pyrrolidine and 5.66 g (9 mmol) vinegar, 9 hydrochloric acid are added successively to it.  After a few minutes, the resulting mixture was added 5 g (1 mmol), α-dimethyl-2.5 cyclohex of sadienone.  Then, the reaction solution is heated overnight at 55 under a nitrogen atmosphere.  After cooling, the resulting reaction mixture is poured into a large volume of ice water, the organic layer is separated and washed successively with dilute acetic acid, several times with dilute sodium hydroxide solution, and finally with saturated sodium chloride solution.  The organic layer is then dried over anhydrous sodium sulphate and evaporated in vacuo to remove the dissolving solvent.  The residue is recrystallized and the mixtures are benzene-hexane and chromatographed on magnesium silicate using benzene as eluent.  Results of elemental microanalysis of the product: Found: CJ3.79i H 5-, 78. .  Cj, And gtOs.  Calculated:, 83; H 6.68.  An example.  Receiving (5a, 6a. ) -6,6a-dihydro-, 8-dimethoxy-6,6-dimethyl-5aH, 1ZN- / 1 / -benzpirano (3,2-B) Xanthen-13 She.  A solution of 100 g (0.66 mol) of sisalicylic aldehyde in BOO ml of benzene is cooled in a nitrogen atmosphere and 80 g (1.15 mol) of pyrrolidine and 60 g (1.0 mol) of acetic acid are successively added to it.  After 15 minutes, Q g (0.33 mol) of C, 4-dimethyl-2,5-cyclohexadienone was added to the resulting mixture at room temperature, and the mixture was heated at 55 ° C overnight.  After cooling, the reaction mixture is poured into a large volume of ice water. The organic layer is separated and washed twice with a 1% aqueous solution of acetic acid, and then three times with a 1 M aqueous solution of sodium hydroxide.  After the final washing of the organic phase with a saturated solution of sodium chloride, the solution is dried over anhydrous sodium sulfate and evaporated in vacuo to remove the solvent.  The residue after evaporation is recrystallized from benzene and hexane.  As a result, 43 g (33 from the theory) of the target compound - (5a | K. ,, 6a-dihydro-4, 8-dimethoxy-6,6-dimethyl-5aH. 1 ЗН710 - / 1 / -benzpirano (3.2-6) Xanthen-13-one, having t. square  23E-2 Gs.  Elemental microanalysis: Found: C 73.79; H 5.62.  Hz GaO: Calculated, J: C 73.83 H 5.68.  Example 6  Preparation of (5ai /,) -6, 6a-dihydro-, 8-diethoxy 6, 6-dimethyl-5aH, 13H- / 1 / -benzpirano (3.2-6-6) xanthen-13 it.  A solution of 1.0 g (2.76 mmol) (5aL /,) -6,6a-dihydro-, 8-DIOXI-6,6-dimethyl-5aH, 13H- (1 / -benzpyrano (3,2-nd) Xanthen-13-one from example 8 in 25 ml of dry hexamethylphospho triamide is treated with 1 g (7.25 mmol) of potassium carbonate and 2 ml (2.9 g, 27 mmol) of ethyl bromide.  The resulting mixture is heated under nitrogen at 70 ° C. overnight.  After cooling, the reaction mixture is poured over 200 ml of cold water.  The resulting product is collected and recrystallized twice from ethanol / water mixture.  In the end, get 0.5 g (from theory) target (5a,) - 6,6a-dihydro-4, 8-diethoxy-6,6-dimethyl-5bN, 13H- / 1 / -benzpirano (3,2-&) xanthen-13-it with t. square  211-213 C.  - Elemental microanalysis: FoundD With 7.92 N 6.51.  GB GB is calculated,% :.  C, 7.62; H 6.26.  Example 7- Preparation of (5 aJy,) -6, 6a igidro-6p-methyl-6-ethyl-ZaN, 1ZN- [1] -benzpirano (3,2-b) xanthen-13-one.  To 220 ml of benzene, 18.2 g (Y8 mmol) of salicylic acid were added successively while cooling in an ice bath.  goto aldehyde, 13.3 g of pyrrolidine and 8.9 g of acetic acid. acid.  Then, 10.0 g (73.5 mmol) of 4-ethyl - "- methyl-2.5 cyclohexadienone was added to the resulting solution.  The resulting mixture was allowed to stir at 55 ° C under a nitrogen atmosphere for a total of 5 days.  Then the reaction mixture is cooled and poured into a large volume of ice water.  The resulting organic layer is separated and washed twice with an aqueous solution of acetic acid, three times with a 1-normal aqueous solution of sodium hydroxide and once with a saturated aqueous solution of sodium chloride.  The washed organic layer is dried over anhydrous sodium sulfate and then evaporated on a rotary evaporator in vacuo to remove benzene.  The residue after evaporation is recrystallized in a mixture of benzene-hexane, and 4.6 g (18.2% of theory) of the title compound, having t. square  189-190C.  Elemental microanalysis: FoundD: C 80.8; H 6, 4% Calculated: C 80.21 J H 5.85P-p, im 8.  Receipt (. , 6a () - 6,6a-dihydro-, 8-dimethox. and-b-methyl-6 h. -ethyl-5aH, 13H- / 1 / -benzpira but (3.2-6) xanthen-13-one.  Under cooling, 18.10 g (119 mmol) of Zmethoxysalicylic aldehyde, 10.64 g of pyrrolidine and 7.12 g of acetic acid are successively added to 180 ml of benzene.  To the resulting solution was added 8.00 g (58.6 mmol) of 4-ethyl-4-methyl-2, logexadienone.  Received-. the mixture is stirred for two days in a nitrogen atmosphere at.  Then the reaction mixture is cooled and poured into a large volume of ice water.  The organic layer is separated and washed sequentially: twice with an aqueous solution of acetic acid, three times with a 1 N solution of sodium hydroxide and once with a saturated solution of sodium chloride. The washed organic layer is dried over anhydrous sodium sulfate and evaporated on a rotary evaporator in vacuo to remove benzene.  The residue after evaporation is chromatographed on a column of silica gel to isolate (5a, 6a) 6,6a-dihydro-4, 8-dimethoxy-6-methyl-6A - ethyl-5aH, 13H- (1) -benzpyranose 3, 2- 6) Santen-13 she.  Recrystallization of the crude product from a mixture of chloroform and methanol gives 2.18 g (9. 2% of theory) of a pure target compound having t. square  203-205С.  Elemental microanalysis: Found,%: C 7.46, H 5,. s Eitt s Calculated C 7.24; H 5.98.  PRI me R 9.  Preparation of (5aC, 6a-dihydrospiro-5aH, 1 MH- / 1 / -benzpirano () xanten-b, V-cycle hexane -1.  7 were added to 85 ml of benzene. 52 (61.6 mmol) salicylic aldehyde 5.5 g of pyrrolidine and 3.7 g of acetic acid.  The mixture is cooled in an ice bath and 5 are added to it. 00 g (30.8 mmol) of 4-cyclohexanespiro-2.5 712 -cyclohexadienone.  The mixture is then left for two days with stirring (under a nitrogen atmosphere), maintaining its temperature at 55 ° C.  After cooling, the mixture is poured into a large excess of ice water, the resulting organic layer is separated and washed twice with an aqueous solution of acetic acid, and then three times with a 1 N sodium hydroxide solution.  After the final wash with a saturated aqueous solution of sodium chloride, the organic layer is dried over anhydrous sodium sulfate and evaporated on a rotary evaporator in vacuo to remove benzene.  The residue after evaporation is recrystallized from methanol.  However, a significant portion of the product remains in the mother liquor.  Therefore, the mother liquor is concentrated and the residue is chromatographed on a silica gel column using benzene as the eluent.  The combined product (recrystallized substance and substance isolated by chromatography on silica gel) is recrystallized from chloroform-methanol to give 3.62 g (32% of theory) of the title compound, having t. square  1b2-1bZ with.  Elemental analysis: Found,%: С 81.13Г Н 6.12.  Cr5 a g Calculated,%: C 81, About; H 5. 99 Example 10.  Preparation of (5e, 6a (p-6,6a-dihydro-6,6-dimethyl-5aH, 13H- / 1 / -benzpirano (3.2-6) xanten-13-one.  A solution of 8.72 g (71, t mmol) of salicylic aldehyde in 60 ml of benzene is cooled in an ice bath and first 8.2 g (115 mmol) of pyrrolidine and then 4.7 g of acetic acid are added to it.  After stirring the mixture for 15 minutes, 4.36 g (35.7 mmol) of 4,4-dimethyl-2,5-cyclohexadienone was added to it, and the reaction solution was stirred in the atmosphere; nitrogen when overnight.  After cooling, the reaction mixture is poured into cold water and extracted with benzene.  The benzene extracts are washed first with a dilute aqueous solution of sodium hydroxide and then with a saturated solution of sodium chloride.  After drying the extract over anhydrous sodium sulfate, the solvent is removed. vacuum.  The crude product obtained in the residue after evaporation was recrystallized from benzene-hexane to give two batches of crystals with a total weight of 4.3 g, which are the target α-isomer.  The mother liquor is evaporated to dryness and the residue is purified by chromatography on a column filled with 100 g of silica gel, 1st degree of activity, using benzene as eluent.  In the process of photo chromatography, three main fractions were eluted from the column: the first fraction contains an additional 0.18 g of pure and 6aiL-M3o measure, the second fraction contains 0.97 T of a mixture (1: 2) of 5aA, - and ba-isomer and target , 6ar isomer, and the third fraction contains 0.66 g of pure target compound, t. e.  (,) - 6,6a-dihydro-6, 6-dimethyl-5aH, 1ZN- / 1 / -benzpirano (3,2-b) xanten-13-one.  This product is crystallized from hexane and an analytical sample is obtained having t. square   WITH.  Elemental microanalysis: Found-, 1: C 80.24; H 5.61.   ° Calculated,%: C 79.98; H 5,  Example 11  Preparation of (S,) -6,6a-dihydro-6,6-dimethyl-5aH, 12H- (1) -benzpirano (3,2-6) xanthen-13-it.  A solution of 50 mHd () -6,6a-dihydro-6, 6-dimethyl-5aH, 1ZN- (1) -benzpirano (3,2-B) xanthen-13-one in 5 ml of toluene is boiled under reflux in nitrogen atmosphere overnight. .  Analysis of the sample of the reaction solution, performed by thin layer chromatography, shows that the conversion of the starting compound to the desired product is complete.  The solvent is then distilled off in vacuo and the residue is passed through a short silica gel chromatography column using benzene as eluent.  The product (kB mg), isolated from the benzene eluate, is recrystallized from the benzene – hexane mixture and as a result 5 mg of the title compound is obtained. square  183 l8t ° C.  This product is recrystallized again from a mixture of benzene and hexane, resulting in a pure title compound with m. square  211212 C.  Example 12  Rastvo. p 100 g (0.66 mol) Zmotoxysalicylic.   the aldehyde in 800 ml of toluene is cooled in an ice bath and 60 g (0.85 mol) of pyrrolidine and 39, g {0.66 mol) of acetic acid are successively added to it.  The mixture is cooled at below O C and kO g (0.33 mol), -dimethyl-2, 5 Cyclohexadienone is added to it with stirring.  The resulting mixture was stirred under nitrogen atmosphere overnight, after which. gradually bring its temperature to room temperature.  Next, the reaction mixture was poured into ice-water and the organic layer was washed successively with two portions of an aqueous aqueous solution of acetic acid, three portions of a 1M aqueous solution of sodium hydroxide, several portions of 1M hydrochloric acid (until the color disappeared), more than three portions mi 1M solution of sodium hydroxide and one portion of a saturated solution of sodium chloride.  During these extraction operations, methylene chloride is added to the organic phase as a co-solvent.  After drying the organic solution over anhydrous sodium sulfate, the solvents are distilled off in vacuo to leave a crystalline residue, which is washed with hexane and air-dried to. constant weight.  As a result, 1 g of crystalline product was obtained (yield 11%) having t. square  175 180 ° C. The melt of the substance immediately crystallizes again as soon as the heat is removed.  A spectral study of this product shows that it is a practically pure target compound containing less than 5 6AA as an impurity. isomer.  All attempts to remove this impurity by careful recrystallization from a mixture of benzene-hexane were unsuccessful.  Elemental microanalysis: Found, 4: C 7h, 97; H 5.76.  . 05  Calculated: C 73.83, H 5.68.  Example 13: Preparation (5AA) , 6aiJ) -6. ba-dihydro-, 8-dimethoxy-6, 6-dimethyl-5aH, 1ZN- (1) -benzpirano (3,2-8) xanthen-13-one.  A solution of 100 mg (5a. , 6a) -6,6a-dihydro- | , 8-dimethoxy-6,6-dimethyl-5aH-1ZN- (1) -benzpirano (3,2-) xanthen-13 it in 5 ml of benzene is boiled under reflux in an atmosphere of azo 15 that overnight.  Analysis of the sample solution by thin layer chromatography shows that the epimerization reaction is complete.  After that, the solvent is distilled off in vacuo and the residue is chromatographed on a short column of silica gel, using a mixture of 10% ethyl acetate in benzene as eluant. .  89 are recovered from the eluate.  mg of product that is recrystallized twice.  from a mixture of benzene-hexane, a pure target compound with m is obtained. square  237-239C.  Example I.  Receiving (,, 12aJs, 13aA. ) -6,6a-12,12a, 13a7l Texahydro, 8-dimethoxy-6,6-dimethyl-5aH,. 13H: / 1 / - benzpyr. ano (3,2-b) xanten-13 she. .  Add 15 to 75 ml of acetonitrile containing 5 water. 0 g p-toluene sulfonate tributyrylamine and C, 0 g of benzoic acid.  To the mixture was added 1.0 g (5aik. , 6a) -6,6a-dihydro, 8-dimethoxy-6,6-dimethyl-5aH, 1ZI- / 1 / -benzpirano (3,2-) xanthen-13-one.  Substrate solubility at 25 ° C is approximately Lg5. mg / m, therefore, the introduced substance remains in the reaction mixture as a suspension. This mixture is placed in the cathode compartment of an electrolytic cell having a mercury cathode (in the form of an iCO mercury reservoir) and a platinum anode.  Whose ke is applied is 1.6 V potency (in c (set with a saturated reference calomel electrode) and the electrolysis process is continued until the sample analysis of the reaction solution, performed by thin layer chromatography, does not show that the reduction reaction proceeds to the end.  Thereafter, the reaction mixture is removed from the electrolytic cell and evaporated in vacuo to remove the solvent.  The residue after evaporation is dissolved in ethyl acetate and the resulting solution is washed successively; three times with IN hydrochloric acid, three times with a saturated aqueous solution of sodium bicarbonate, three times with 1 N hydrochloric acid, and two times with a saturated aqueous solution of bicarbonate. rub and once with water.  Analysis of the product by high pressure liquid chromatography shows that. 65 (For. Cba-,.  13aА) -6,6а, 12,12а, 13а, Y-hexahydro-4, 8-dimethoxy-6, 6-dimethyl-5aH, 1 ЗН7 6 - / 1 / -benzpirano (3,2-b) xanthen-13 -she is.  Ethyl acetate is distilled off in vacuo, and the residue obtained is dried to constant weight.  This product is recrystallized from a mixture of methanol and chloroform, as a result of which the target product having a purity of 90% is obtained with a yield of 50% from theory.  Example 15- Preparation of (5aH, 6adL, 12a, 13aj2,) -6, 6a, 12,12a, 13a, U-hexahydro, 8-dimethoxy-6,6-dimethyl-5aH, 13H- / 1 / -benzpirano ( 3,2-b) Xanthen-13 she.  Using a procedure similar to that described in Example 1, a mixture of 0.8 g of lithium perchlorate and 0 ml of glacial acetic acid in 75 ml of acetonitrile, containing 5% water, is prepared.  To the mixture was added 1.0 g (. ,, 6a-dihydro-, 8-dimethoxy-6,6-dimethyl-5aH, 13H- / 1 / -benzpirano (3,2-) xaiten-13-one.  The mixture thus obtained is subjected to electrolytic reduction at the mercury cathode and the platinum anode at 25 ° C and a constant electric potential (1.5 V) established relative to the saturated calomel electrode used as the reference.  The monitoring of the completeness of the electrolytic reduction reaction is carried out by thin layer chromatography.  Further processing of the reaction mixture to isolate the product. recovery and recrystallization of this product from. chloroform-methanol mixtures result in a target (5aJv ,,.  , 12ajb, 13a / 5. ) -6, 6a, 12,12a, 13,1 -hexagidro-, 8-dimethoxy-6,6-dimethyl-5aH, 13H- / l / -benzpyrano (3,2-B) cangen-13-one in the form lamellar crystals with cream color.  The yield of the product is 6S% of theoretically possible, and the product has a degree of purity  T. square  This product 235-2 5С.  Example.  sixteen.  Receiving {5aJ,, 12ai, 13aJL. ) -6,6a, 12, 12a, 1 Za, 14-hexahydro, 8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) -benzpirano (3,2-8) xan-.  Tbn-13-she.  Using a technique similar to that described. th in example 2, to 50 ml of N, N-dimethylformamide containing. 5 water added 2 g of benzoic acid and such amount of tetrabutylammonium perchlorate, which is sufficient to achieve a 0.2 M concentration of 177 pa.  Then, 100 mg (5at, 6aA) was added to the mixture. ) -6,6a-dihydro-4, 8-dimethoxy-6,6-dimethyl-5aH, 13H- / 1 / -benzpirano (3.2-6-6) xanthen-13 it The resulting mixture is subjected to electrolytic reduction at the mercury cathode at 25 ° C and a constant (ratio of 1.5 V) electric potential (measured in comparison with a reference saturated calomel electrode).  The subsequent treatment of the reaction see and recrystallization of the isolated crude product yields the desired (,, 12a (L, 1 3a. JO-6,6a, 12 12a, 13a, 1 + -hexahydro, 8-dimethoxy-6, 6-dimethyl-5aH, 13H- / 1 / -benzpirano (3, 2-6) xanthen-1 Zone with Exit 70 %  Example 17  Getting (SaJv, 6a J. ,, 1) -6,6a, 12, 12a, 13a, 1 i-hexahydro, 8-dimethoxy-6,6-dimethyl-5aH, 1ZN- / 1 / -benzpirano (3, 2-b) xanthen-13 she is.  , Using the technique.  similar to that described in Example 1, tetrabutylammonium chloride in an amount sufficient to achieve a 0.1 M concentration is added to a mixture of 6O ml of methanol and 8 ml of glacial acetic acid.  Next, 100 mg of () -6 was added to the mixture. , 6-dihydro-4,8-dimethoxy-6, 6a-dihydro-4,8-dimethoxy-6,6-dimethyl-5aH, 1ZN- / 1 / -benzpirano (3,2-b) xanten-13 it .  The mixture prepared in this manner is subjected to electrolytic reduction at the mercury cathode at 25 ° C and constant 1, k V sweat. Potential (in comparison with standard saturated calomel electrode).  Subsequent treatment of the reaction mixture and recrystallization of the isolated crude product yields the desired (a,. .  ) -6,6a, 12,12a, 13a, 14-hexahydro o-k, 8-dimethoxy-6,6-dimethyl-5aH, 1zP- / 1 / -benzpiraio (3.2-6) xanten-13 it with yield 85% of theory.  E and m 18.  Receive (5a (. , 6a) -, 12aJL, 1 For -) - 6, 6a-12,12a, 1 For, 1t-hexahydro, 8-dimethoxy-6.6 dimethyl-5aH, 13H- / 1 / -benzpirano (3.2 -B) Xanthen-13 she.  Using the procedure of Example 1, to the mixture of 75 ml of acetonitrile, containing 5% acetic acid, was added methylate trioctylammonium chloride in an amount sufficient to create a 0.1 M concentration.  To received,; the mixture was then added 200 mg (. ba-dihydro-, 8-dimethoxy-6,6718-dimethyl-5aH, 13H- / 1 / -benzpirano (3,2-i) xanten-13 it. The mixture thus prepared is subjected to electrolytic reduction at the mercury cathode at a constant potential of 1.6 V (as compared with a reference saturated calomel electrode).  Analysis of the reaction solution by high-pressure liquid chromatography shows the presence of the target (, baha, 13aA) -6,6a-12,1a, 13a, th-hexahydro, 8-dimethoxy-6,6-dimethyl-5aH, 1ZN- / 1 / -benzpirano (3.2-6) Xanthen-13, in the amount corresponding to the yield.  Example 19  Receipt.  (, 6a J-,,) -6, 6a, 12,12a, 1 Over, 1 it-hexahydro, 8-dimethoxy-6, 6-dimethyl-5aH, 13H- (1) -benzpyran © (3.2 -6) Xanthen-13 she.  Using the procedure of Example 1, tosylate M, M-diisopropylztilamine in an amount of 0.1 M was added to a mixture of 67 ml of acetonitrile containing 5% water and 5.5% acetic acid, then 100 mg (5aL, 6a) -6,6a-dihydro-A, 8-dimethoxy-6, 6-dimethyl-5aH, 1ZN- / 1 / -benzpirano (3,2-6) xanthene.  The mixture thus prepared is subjected to electrolytic reduction at the mercury cathode at a constant potential of 1.5 V (compared with a reference saturated calomel electrode).  Analysis of the reaction mixture by high pressure liquid chromatography shows the presence of the target (, 6a (L, /, 13ai) -6.6a, 12L2a, 13a, 1-hexagidro-4, 8-dimethoxy-6,6-dimethyl-5aH, 13H- / 1 / -benzpirano (3.2- &) xanthen-13-it in the amount of 60-65% of the output.  Example 20  Receiving (aji bal. ) -6,6a-dihydro-3,9 dicyano-6,6-dimethyl-5aH, 1ZN- / 1 / -benzpirano {3,2-6) xanten-13 it.  As in Example 1, a reaction between α-cyanosalicylic aldehyde and 4, α-dimethyl-2.5 cyclohexadienone is carried out in the presence of pyrrolidine and acetic acid.  The product is isolated and purified in accordance with Example 1.  Get (5a () v. ,, 6a-dihydro-3, 9DITsiano-6,6-dimethyl-5aH, 13H- / 1 / -benzpirano 3,2-xanthene13-it with a yield of 50% of theory.  Example 21  Preparation (), 13ad) -6,6a, -12J2a, 13a, -hexahydro-4,8 dimethoxy-6,6-dimethyl-5aH, 13H- / 1 / -benzpirano (3,2-6) xanthen-13 it .  Using the procedure of Example 1, a mixture of 2.57 g of tetrabutylammonium perchlorate and 2.5 g of benzoic acid in 50 ml of toluene and 25 ml of methanol was prepared.  300 mg (5a (K. ,, 6a-dihydro-, 8-di-methoxy-6,6-dimethyl-5aH, 1ZN- / 1 / -benzpirano (3,2-6) xanten-13 it.  The mixture thus prepared is subjected to electrolytic reduction at a mercury cathode at 25 ° C and a constant 1.6 V potential in comparison with a reference saturated calomel electrode.  Further processing of the reaction mixture and recrystallization of the isolated crude product yields the desired. , 12a. k; i3a v) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) -benzpirano (3,2-6) xanthene 13-she with the release of 85% of theory.  Example 22, Preparation of (5aL, | 6a 12a / Za) -6.6a, 12,12a, 1 Za, Y-goxagydro, 8-dimethoxy-6,6-dimethyl-5aH, 13H7 / 1 / -benzpirano (3 , 2nd) Xanthen-13-she.  Using the procedure of Example 1, to a mixture of 75 ml of acetonitrile containing 5% acetic acid and 5 water, is added tetra n-hexamylammonium chloride in an amount sufficient to create a 0.1 M concentration.  Then, 200 was added to the mixture. mg (,) -6,6a-dihydro-and, 8-dimethoxy-6,6-dimethyl-5aH, 1ZN- / 1 / -benzpirano) xanthen-13-one, after which this mixture is subjected to electrolytic reduction at the mercury cathode at and a constant, 1.7 V potential (in comparison with a reference saturated calomel electrode).  Analysis of the reaction solution by high performance liquid chromatography.  pressure indicates the presence of target 4 (,,, 13a) -6.6 12, IZa, 13a, 1-hexahydro, 8-dimets si-6,6-dimethyl-5aH, 1ZN- / 1 / -benzpirano (3, 2- S) Xanthen-13-it with the release of 65-701 from the theory.  The compounds of the formula have an effective anti-androgenic effect in doses of 0 mg per kilogram of body weight (meaning daily dose).  Preferably, the drug forms are produced in such an additive when the dose unit (e.g., one tablet or capsule) contains 1-500 mg of the active compound.  The most preferred, in particular, are those unit dosages of the preparation, which contain 50-250 mg of active ingredient.  Preferably, the compounds of formula 1 are administered orally.   The anti-androgenic activity of these compounds is illustrated by the results of standard biological tests in rats using castrated, immature male rats as test animals.  Thus, biological tests are carried out using immature male rats, usually 21 days old. which are subjected to bilateral (bilateral) castration and left without treatment for a period of three days.  This provides sufficient time for the metabolism of endogenous androgens and for atrophy of the secondary genital organs (first of all).  Next, neutered male rats are divided into at least three treatment groups.  Ten rats were injected subcutaneously, once a day, with 0.02 mg of testosterone propionate (PT) suspended in corn oil.  These rats serve as a control group of animals stimulated with androgenic substance, t. e.  as an androgen-stimulated control group.  Another group of five rats were injected subcutaneously, once every day (for the entire duration of the experiment), pure corn oil, so that this group of rats constitutes the control group of castrates.  A third group of rats participating in the tests consists of five individuals, each of which receives subcutaneously 0.02 mg PT and the corresponding test compound, either by oral administration or by subcutaneous injection, once a day.  A separate group of experimental animals is used to test each compound subjected to a biological activity test and each dose level.  All animals are treated without interruption for seven days.  On the eighth day, all rats that are 23 days old by this day are killed (slaughtered) —and 219 are dissected — in the autopsy procedure (autopsy), the nominal vesicles and ventral prostate glands, which are taken, are removed from the corpses. hang up.  The weight of the seminal vesicles (SP) and ventral prostate glands (VSG) of the control group of castrates is subtracted from the weight of the SP and HPV androgen stimulated control group in order to determine the degree of androgenic stimulation, which occurred as a result of exogenous | Administration to control group PT rats. All SP and VPI of each experimentally group of animals that were injected with the test compounds were subtracted from the weight of the SP and VSW of the androgen-stimulated group of rats, and the resulting difference is divided by the weight of the corresponding organ, which occurred as a result of one steron-prescription test in rats.  The resulting partial 722 from the division is expressed as JB percent and is called the degree of inhibition or percent inhibition.  The effect of administering test compounds or, in other words, the effect of each compound administered on the effect of androgenic stimulation caused by testosterone propionate, is proved and illustrated by the lack of gain in endocrine glands in rats, along with the androgen stimulator (testosterone propionate) the test compound tested for anti-androgenic activity, compared with the weight gain of those.  same organs in rats subjected to androgen stimulation of testosterone propionato alone.  The table shows the androgen inhibiting activity of the compounds of formula 2.

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.. 4G The formula of the invention The method of obtaining the derivatives of hexahydrobenzpyraoxantenones of the general formula O, Rn where, R is Cj-C 1 alkoxy, both radicals being identical and symmetrically arranged, R and R -methyl, X, X, X, Y and Y is hydrogen atoms, provided that X and X are in -configuration or in -configuration, and the radical R characterized in that the compound of formula 7 where R, R, R "Xc and Xd have the indicated values is subjected to electrochemical reduction in organic or aquatic environment at ambient temperature at the mercury cathode in the presence of Wii proton source with a pKa value of 2-6 and an electrolyte selected from the group which includes alkali metal salts, quaternary ammonium salts with a content of carbon atoms in the cation moiety 10-25 or tertiary amine salt with a content of carbon atoms in the cation moiety. Sources of information taken into account in the examination 1. R. Elderfield. Heterocyclic compounds. M., ed. And-l. , E5, t. 2, p. 271.

Claims (1)

Claim A method of obtaining derivatives of hexa hydrobenzopyranoxanthenone with general where, R is C (-C ^ -alkoxy, both radicals being identical and symmetrical, R and R-methyl, · X, X, X, Y and Y are hydrogen atoms, provided that X and X are in the -configuration or in the -configuration, and the radical R is about t'l and h'a, and with the fact that, B1E ₂ where RR ^ .R ^ X _c and XJ have the indicated meanings, they are subjected to electrochemical reduction in an organic or aqueous organic medium at ambient temperature at the mercury cathode in the presence of a proton source with a pKa value of 2-6 and an electrolyte selected from the group which includes 10 alkali metal salts, quaternary ammonium salts with carbon atoms in the cationic residue 10-25 or tertiary amine salts with! 5jeM carbon atoms in the cationic residue 721.