The method of oxidation5steroid alkene, connection method for obtaining compounds

 

(57) Abstract:

Describes a new way of oxidation5-steroid alkene of General formula I, where Y, X, Z specified in paragraph 1 of the formula, wherein a5-steroid alkene of General formula I is treated with hydropredict in a solvent in the presence of a catalyst based on ruthenium. Also described is a method of obtaining compounds. The technical result is to simplify the process of obtaining the desired products. 3 C. and 25 C.p. f-crystals.

The present invention relates to a new method for the catalytic oxidation of compounds containing allyl group, in which use catalysts based on ruthenium. The method is generally suitable for the oxidation of compounds containing allylic hydrogens or alcohols, and in particular for the oxidation of 5-steroid compounds.

Background of the invention

The principal mediator of androgenic activity in some target organs, such as prostate, is a 5-dihydrotestosterone ("DHT"), educated locally in the target organ by the action of 5-reductase, which converts testosterone to DHT. The result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone ("T") and the ski manifestations, like common acne vulgaris, seborrhea, hirsutism in women, androgenic alopecia, including alopecia in women and men, and benign prostatic hyperplasia. Inhibitors of 5-reductase will serve to prevent or reduce symptoms of hyperandrogenic stimulation in these organs. See, in particular, U.S. patent N 4377584, published on March 22, 1983, and N 4760071, published on 26 July 1988, successors which is Merck and Co., Inc. In addition, it is now known that there is a second isoenzyme of 5 - reductase, which interacts with skin tissues, mainly in scalped tissues. See, for example, g.Horris, et al. Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (Nov. 1992). Isoenzyme, which mainly engages in the skin tissues, denoted generally as 5 - reductase 1 (or 5-reductase type 1), whereas isoenzyme, which mainly engages in the tissues of the prostate, is designated generally as 5-reductase 2 (or 5 - reductase type 2).

Oxidation-5-steroidal alkenes in the appropriate enone is an important stage in the synthesis of steroid end products, suitable as an inhibitor of 5-reductase. For the oxidation of allyl groups previously used ocil is m necessary silikagelya chromatography. The present invention provides an improved alternative method of oxidation-5 - steroidal alkenes, which is easy to implement and acceptable to the environment. In addition, the yield and purity of the oxidized intermediate compounds obtained by this method correspond to the yield and purity, which were obtained using previously known methods of oxidation, or surpass them.

The invention

The new method of this invention involves the oxidation of compounds containing allylic alcohol group or allylic hydrogens in the appropriate enone using a catalyst based on ruthenium in the presence of hydroperoxide. This invention, in particular, includes the transformation of-5-steroidal alkenes in-5-7-ketosteroids alkenes using a catalyst based on ruthenium in the presence of hydroperoxide. As an example, the new method can serve it the following option:

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The compounds of formula II are useful as intermediates 7 - substituted 3-keto-4-azasteroid compounds, an example of such, which are inhibitors of 5 - reductase. Inhibitors of 5 - reductase are suitable for the treatment of hyperandrogen hirsutism women androgenic alopecia, and in the prevention and treatment of prostate cancer.

Detailed description of the invention

The new method of this invention includes the discovery that steroid compounds containing C5-C6double bond (i.e.- 5 - steroidal alkenes can be oxidized to the corresponding 7-catasetinae by treatment with hydroperoxide in the presence of a catalyst based on ruthenium.

Using the same method, compounds containing allylic alcohol group can be similarly oxidized to their corresponding kotoni. For reference: the standard numbering of the steroid structure with the unsubstituted core and the letter of the rings is the following:

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Surprisingly it was found that this method of oxidation can be implemented using any catalyst based on ruthenium. In this area there are many catalysts based on ruthenium, and such catalysts based on ruthenium can be used in this way. Examples of catalysts based on ruthenium, which can be used in this way include: RuW11O39SiNa5, RuCl3, RuCl2(PPh3)3, Ru(ACAC)3, Ru(Dima>iRu(H2O)W11O39however , not limited to only them. "TPP" is tetraphenylporphin; "ACAC" is acetylacetonate; "BP" is bipyridines. Catalysts based on ruthenium described, for example, in the source J. Am. Chem., Soc., Vol. 112, 6025 (1990); S-I. morahashi, Tetrahedron Letters, Vol. 34, 1299 (1993).

Use, in particular, the catalyst, based on the sodium tungstate-ruthenium and more specifically RuW11O39SiNa5. In this reaction, the use of catalytic amount of ruthenium compounds. Professionals in this field know about the use of catalytic amounts of reaction catalysts which may be used may vary depending on the reaction scale and characteristics of the applied catalyst based on ruthenium. The approximate amount of the catalyst based on ruthenium is in the range from about 0.05 to 5 mol. % and especially from about 0.5 mol.% catalyst on mol.% the source material, but are also acceptable options outside of this range.

The original alkene is treated with hydropredict in the presence of a catalyst based on ruthenium to turn into a corresponding northward. In this area there are many gioria can be used in this way, include Gidropress tert-butyl (tert-BuOOH), Gidropress cumene, hydrogen peroxide and benzoyl peroxide, but not limited to, preferred is tert-BuOOH. The method uses a number of gidroperekisi sufficient for complete oxidation, for example, at least about 2 moles and preferably from about 8 to 10 moles per mole of the starting material. At this stage of the method can be used any commercially suitable solvent or combination thereof, for example alkanes, ethers, alcohols, halogenated solvents, water, etc. many Examples of solvents that can be used include toluene, ethyl acetate, hexane, chlorobenzene, heptane, tert-butyl methyl ether (MTBE), benzene, acetonitrile, cyclohexane, methylene chloride, 1,2-dichloroethane and tert-butyl alcohol (t-BuOH), or combinations thereof, but is not limited to only them. When the catalyst is used RuW11O39SiNa5the preferred solvent is heptane. When using as a catalyst RuCI2(PPh3)3preferred solvents are chlorobenzene or benzene.

The method of oxidation can be performed at a temperature features between from about 5oC and up to about 50oC, and most preferably at about 15oC. the Reaction may be carried out at any pH, particularly at acidic pH values, and in particular at a pH of about 1. Before adding tert-BuOOH by adding an aqueous solution of acid, such as sulfuric acid, can be adjusted pH of the reaction mixture. The reaction is preferably carried out in an inert atmosphere, for example nitrogen or argon, although it is not required.

-5 - steroidal alkenes, which can be used in this way are known in this field. For example, see these listed and available from Sigma Chemical To.

One variant of the present invention includes a step of processing the compounds of formula 1:

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hydropredict in the presence of a catalyst based on ruthenium in the solvent for the formation of compounds of formula II:

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in which Y is a hydroxy-group, esterified hydroxy-group, keto or atelectasis, X is-CH2-, -NH - or-N(CH3) - or-N-2,4-dimethoxybenzyl, and Z is

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The oxidation reaction is not affected by the Deputy in 16 - or 17-position of the steroid and so "A" can be any synthetically feasible for the selection of the substituent in the 16 and 17-positions of the steroid. Typical examples of "A" include: -H; keto(=O); protected hydroxy for example, dimethyl-tert-butylsilane, trimethylsilyloxy, triethylsilane, three-isopropylethylene, triphenylsilane; acetate, hydroxy; protected amino, for example, acetylamino; amino; C1-10alkyl, for example methyl, ethyl, 1,5-diethylhexyl, 6-methylhept-2-yl-cholestanol with a 17-side chain, pregnant or stigmasterol with a 17-side chain; aryl-substituted C1-10-alkyl, such as omega-phenylpropyl, 1-(chlorophenoxy)ethyl; arylcarbamoyl C1-10alkyl, for example 2-(4-pyridylcarbonyl)ethyl; C1-10alkylsulphonyl, for example, isobutylketone; arylcarbamoyl, for example, phenylcarbinol; afrosamurai C1-10-alkyl, for example, 1-methoxyethyl, 1-ethoxyethyl; Ketobemidone C1-10-alkyl, for example, 1-ketoacyl; heterothermy C1-10-alkyl, such as omega-(4-pyridyl) butyl; carboxy; esters of carboxylic acids, for example, esters of C1-10-alkylcarboxylic acids, such as carbomethoxy; carboxamide, for example, C1-10-alkylcarboxylic or aralkylated, such as N, N-diiso-propylnitrosamine, n-tert-butylcarbamoyl or N-(diphenylmethyl) carboxamide; carbamates, such as C1-10-allylcarbamate, especially the Tr is stitely, selected from ethyl, methyl, trifloromethyl or halogen (F, Cl, B, I); urea, for example, C1-10-alkylcarboxylic, such as tert-BUTYLCARBAMATE;

C1-10-alkylcarboxylic, for example, tert-BUTYLCARBAMATE; ethers, for example, n-Butylochka, atlantal; substituted and unsubstituted akrilovye esters, such as: chlorphenoxy, methylphenoxy, phenyloxy, methylsulfinylphenyl, pyrimidinone etc.

The term "alkyl" includes an alkyl group with a straight or branched chain, and "aryl" includes phenyl, pyridinyl and pyrimidinyl.

Specialists in this area known protective group for hydroxy and amino, can be used any such protective groups. Suitable protective groups for hydroxy are, for example, acetate, benzoate, ether and silyl protective group. Standard silyl protective groups have the General formula: -Si(Xa)3where each Xagroup is independently alkyl or aryl group, and include, for example, trimethylsilyl, triethylsilyl, tri-ISO-propulsion, triphenylmethyl, and tert-butyl-di (Xin)-silyl, where Xinis stands, ethyl, isopropyl or phenyl is scrap, O-alkyl or O-aryl, and include, for example, N-tert-butoxycarbonyl. See also the description of the protective groups in the source Protective groups in Organic Synthesis, T. W. green et.al. (John Wiley and Sons, 1991).

Specialists in this field it is clear that when Y is an esterified hydroxy-group are substituents, for example, those represented by formula III.

(III)

where Xdcan form any synthetically possible group of ester. The method is not limited to the choice of a particular group of ester for Y. Typical examples Xainclude alkyl straight or branched chain, for example, C1-18-alkyl, phenyl, mono or disubstituted phenyl, where the substituents include, for example, halogen, aloxi and amino.

To obtain 7 - substituted, 4-azasteroid compounds and in particular those that are inhibitors of 5-reductase, is suitable intermediate compound II. Examples of such compounds include compounds presented in U.S. patent N 4377584 and 4760071; WO 93/23419 and W0 93/23420. More specifically, compounds that can be obtained from the intermediate compound (II) include compounds of General formula IV:

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in which R is H or stands, Z is
is a (Pr), of isopropyl (i-Pr), n-butyl (H-Bu), sec-butyl, ISO-butyl, tert-butyl (tert-Bu), etc.; C3-6-cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and allyl. Methods for such compounds, for example, in U.S. patent N 5237064, WO 93/23419 and WO 93/23420 and the PCT application having serial number US 94/12071.

The following is an example of a synthesis scheme, showing how it is possible to obtain the compounds of formula IV.

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The starting materials for this method are usually 3-acetoxyethyl-5-ENES, which are known and available in this area.

Z is

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The term "A" described above and can be any Deputy, preferably inert and does not affect the specific reaction conditions for each stage are presented in the above reaction scheme.

Group A can be protected by a hydroxy-group or protected amino group, which is subjected to the specified reaction sequence and then it is removed, or it can be removed during the course of the particular stage to ensure that it was not an obstacle to the specified reaction. When A is, for example, -O-TBDMS, i.e. tert-butyldimethylsilyloxy, teroid 7, so the next stage was carried out with 16 - or 17-OH-connection.

The original group A can also be a precursor to the final desired group A and may be also simultaneously turned on one stage. For example, when the group contains A double bond, for example, similar stigma-Sterol, a double bond in a 16 - or 17-side chain can also be oxidized during the formation of scaricati in the transition from 5 to 6.

As shown in the above reaction scheme, "Alk", the Deputy can usually be entered in ring B 4-azasteroid by using the reactions of addition of ORGANOMETALLIC carbonyl, for example, the Grignard reaction in which 7-carbonyl group can interact with a Grignard reagent containing the "Alk" as the R radical in RMgX. The conditions of the Grignard reaction are conventional and include, for example, the use of methyl-, allyl - or cycloalkylation, ethylacetamide, cyclopropylmagnesium, etc., the Grignard Reagent is used preferably with CeCl3. Used dry solvents include, for example, tetrahydrofuran (THF), diethyl ether, dimethoxyethane and di-n-butyl ether. The reaction is carried out in anhydrous medium, usually in the range of temperature shall be used other reactions of addition of ORGANOMETALLIC carbonyl, for example, using lithium and zinc ORGANOMETALLIC reagents, which are known in this field.

Then adduct using, for example, aluminiumprofile and cyclohexanone (oxidation Oppenauer) oxidizes when heated in a flask under reflux in toluene solvent to obtain 7-alkyl-4,6-Dien-3-one . Other reagents that can be used are, for example, aluminum ethylate or tert-butyl aluminum. Other solvents that may be used include, for example, methyl ethyl ketone (MEK) and xylene. The temperature is usually in the range from about 60oC to about 120oC, the reaction is carried out in anhydrous conditions and usually for its completion should be from about 2 to about 24 hours.

Then, Dien-3-one is converted into 4-ene by treatment with palladium on carbon, DBU and cyclohexanol in a solvent such as ethanol.

Then open the loop A, for example, by treatment with potassium permanganate, periodates sodium, for example, tert-butyl alcohol at a temperature of 80oC to obtain the corresponding SECO-acid . Other oxidizing agents that can be used wcll (MeOH) and CH2Cl2. For the full implementation of the reaction usually requires 2 to 4 hours.

SECO-acid C2-4-alanovoy acid, for example acetic acid (HOAc), treated with ammonium acetate at a temperature of about 15-30oC, and then heated in a flask with reflux condenser during the time from 2 to 4 hours. After cooling to approximately 50-70oC add water and in the mixture contribute seed to induce crystallization Yong-lactam .

Hydrogenation Yong-lactam carried out using a catalyst which is a noble metal; for example, Pd(OH)2, PtO2Pd on carbon, Ph on carbon or Ph/Al2O3and preferably with the use of Ph on carbon or Ph/Al2O3in C2-4-alanovoy acid, for example acetic acid, or alcohol, such as ethanol, or ethyl acetate at a pressure of hydrogen 50-70 psi (3,5155-4,9217 kg/cm2). The reaction is carried out at a temperature of 15-25oC during the time from 8 to 12 hours, and then the temperature was raised up to 50-70oC, and hold up until the reaction is completed fully. Filtration to remove the catalyst and the filtrate concentrated to dryness. Then the product can be cleaned, for example by recrystallization.

oC and rapid stirring until then, while the reaction will be completed in full, usually within a time of about 20-30 hours.

Typical experimental methods using the new method described in detail below. These techniques serve only as examples and should not be construed as limitations of the new method of this invention.

Example 1

Getting 4,7 - dimethyl-4-Aza-5 - cholestan-3-

Stage 1 (see diagram and table. at the end of the description).

In a three-neck flask with a volume of 2000 ml was added to the dihydrate of sodium tungstate (3.3 grams), metasilicate sodium (0,315 g) and 70 ml of water and stirred to obtain a homogeneous solution. The solution was neutralized (pH 6-7) concentrated sulfuric acid (0.45 ml). Adding acid at the 4oC noted the heat. Added hydrate trichloride ruthenium (240 mg) and the mixture was mixed for 10 minutes. To the catalytic mixture added cholesterylester (78,1 g) and heptane (300 ml). The mixing speed was 225-275 rpm when peripodial equal to 15-20oC by cooling water bath. After the induction period of 5-15 min, temperature loading slowly started to rise. The reaction mixture was stirred until then, remained less than 1.5 wt.% s.m. (source material) and less than 2% of the intermediate 7-hydroxycholesterol, for about 20-24 hours.

The reaction was controlled by the UMC osnovnoi column, when the ratio of acetonitrile to water 90:10, flow rate = 1.5 ml/min, UV detection at 200 nm. Retention time : tR(hold time) cholesterolaemia = 17,0 min, tR7-ketocholesterol = 7,8 min, tRintermediates 7-hydroxyperoxide, 7-tins = 6,8, 6,9, 7,0, 8,2 minutes Impurities, eluruumina through the 18th and 19th minutes, are 7-tert-BuOO-cholesterylester.

To the reaction mixture was added 550 ml of MEK, 390 ml of water and 39 g of sodium sulfate. The mixture was heated to 70oC up until gone admixture of Indiana, about 3 hours. The reaction mixture is cooled, and then transferred into a separating funnel, and the fraction of the aqueous layer, and then the organic layer was washed with 100 ml of 1% brine. Then MEK and tert-BuOH was removed by azeotropic distillation with heptane (after adjusting the source end is, the fact was established by analysis of GC (gas chromatography).

By gas chromatography using column HP-5 35oC and a flow rate of 0.5 ml control heptane on the content of MEK and tert-BuOH. tRMEK=4,9 min, tRtert-BuOH=5,3 min, tRheptane=7,7 minutes, the Volume was set equal to 350 ml, cooled to -5oC and was filtered, washed twice with 150 ml of heptane at 0oC. After drying, the product was received, the output 62% (total of 51.5 g, 94 wt.%, 97 A%) as not quite white solid connections. "A%" is % of the area.

The melting temperature (t p): 155-157oC; NMR (1H, 300MN, CDCl3): 5,70 (c, 1H), 4,7 (m, 1H), 2,5-0,8 (m, 43H), and 0.6 (s, 3H).

(See further stage 2 at the end of the description).

Anhydrous cerium chloride (16.6 g) was stirred in suspension in THF (150 ml) at 20oC under nitrogen for 2 hours.

The cerium chloride obtained in the form of heptahydrate and dried in a vacuum at a temperature furnace 170oC during the period of time from 3 to 4 days. The dried cerium chloride, as shown by the analysis of TG (Tg), had a weight loss of 0.7%. After 2 hours, removed the sample suspension and under the microscope watched small needle crystals. To the suspension was added the Grignard reagent (160 ml) and education is (C) added Keon (60 g with a purity of 95%, as shown by quantitative analysis of 57 g) in THF (150 ml) for 50 minutes adding the ketone to the Grignard reagent watched the heat, ectothermy regulated by the speed of adding. To ensure complete dissolution, before adding a solution of the ketone to the Grignard reagent solution of the ketone in THF followed heated to 30oC.

The reaction course was monitored by HPLC (liquid chromatography under high pressure). To 10 ml of 0.1 N HOAc was added 0.5 ml of sample and then use CH3CN diluted to 50 ml. of HPLC Conditions: (Phenyl column ZORBAXCH3CN, water, phosphoric acid; gradient elution from 75:25:0.1 to 90:10:0.1 V for 18 min flow Rate=1.5 ml/min, UV detection at 200 nm). Retention time: tR3,7-diol=5,6 and 5.9 min, tRoriginal ketone=10,9 min, tRthe intermediate 7-OH, 3-OAc=9,8 min and 10.8 min 95% of the area corresponded to 3.7-diolo (approximately 85 mg/ml). (Note: any remaining starting material or intermediate compounds can be converted into a product using an additional amount of Grignard reagent).

After completion of the reaction, the reaction mixture is quickly cooled by adding it to the mixture rastermaster. (Note: the rate of addition should be adjusted carefully to keep the internal temperature below 10oC).

A two-phase mixture was mixed for 30 minutes and kept for 10-15 minutes for the appropriate separation of phases. the pH of the aqueous layer was about 2. The organic phase is separated, washed with water (200 ml, pH 3 after washing) and a saturated solution of NaHCO3(240 ml, pH 8 after washing). This has given the opportunity to get a 750 ml organic layer, which contained 66 mg/ml diol, the output of 49.5 g (93%). The aqueous layer contained less than 1% of the product.

The load was concentrated in vacuo to 300 ml (100-200 mm), diluted with toluene to 600 ml) and again concentrated to 360 ml. changing the solvent to toluene considered complete when, as shown by gas chromatography, % area THF was < 2% relative % of the area of toluene (note: the first 200 ml of distillate had a tendency to foam at low pressures. After the formation of this phase was completed, the vacuum should be reduced to 100 mm, the distillation Temperature is slowly increased from the 20oC to approximately 45oC when changing the solvent to toluene has come to an end).

Samples of the distillate to use bavili up to 1 ml with methanol. Conditions for gas chromatography: (HP-5 column (25 m, 1D of 0.32 μm) injector with a heating unit, the isotherm at 35oC, flow rate = 0.5 ml/min), * tRTHF = 6.2 min, tRtool = 10,1 minutes Final analysis was conducted using a sample of the load. *MeOH tR= 5,5 minutes

The organic layer contained RUR 134.4 mg/ml diols, the total yield amounted to 48.4 g (90%). (note: before passing the next stage KF load should be less than 100 µg/ml). (See further Stage 3 at the end of the description)

To the toluene solution of diol (256 ml, 118 mg/ml) was added 2-butanone (126 ml) and isoproxide aluminum (18,9 g). The solution was heated in a flask with reflux condenser (92oC) under nitrogen. The reaction course was monitored by HPLC.

Before adding isoproxide aluminum by gas chromatography downloading analyzed for the content of 2-butanone. A sample in an amount of about 0.1 ml was diluted with MeOH to 1 ml. Conditions for gas chromatography:

HP-5 column (25 m, 1D of 0.32 μm) injector with a heating block at 250oC isotherm at 35oC, flow rate = 0.5 ml/min, tR2-butanone = 6,1 min, MeOH = 5,5 min, tRtoluene = 10,1 minutes KF original mix 70 µg/ml.

0.1 ml of the test reactio [25 cm phenyl column ZORBAX; CH3CN:H2O with 0.1% phosphoric acid, gradient elution from 75:25 to 90:10 for 18 min at a speed of up to 22 min 90: 10, flow rate = 1.5 ml/min, UV detection at 210 nm]; tRsource diols = 5,4 min, and 5.8 min; tRintermediate - 4-Aenon = 6,4 min, tRdienone = 12,1 minutes

The reaction was considered complete when the original diol was less than 3% of the area (8 hours). After completion of the reaction load was cooled to 15-20oC and then quickly cooled 3N HCl (120 ml). A two-phase mixture was mixed for 20 minutes and then provided her assertion. Removed the lower aqueous layer and the organic layer washed with 5% NaCl (120 ml). The load was concentrated in vacuo to half volume (40-60oC at 150 mm). By distillation of the boot removed the excess 2-butanone. Level 2-butanone in the final loading was < 2% relative to toluene (using gas chromatography) and KF 60 g/ml.

The toluene solution was treated with concentrated hydrochloric acid (3.5 ml) at 25oC under nitrogen. The reaction mixture was analyzed by HPLC to until the intermediate tertiary alcohol completely turned into Danon (approximately 1 hour). The solution was washed with deionized water (60 to flow in the reverse direction, if the experiment is carried out in the course of time more than 8 hours). The obtained red solution (128 ml) contained 202 mg/ml dienone, out - of 25.9 g (90%). (See further Stage 4 at the end of the description).

Toluene solution of dienone (150 ml 214,6 mg/ml) was diluted with ethanol (120 ml) and cyclohexene (120 ml) and DBU (of 0.62 ml). To the mixture was added 5% palladium on carbon (9.0 g wetted with 50% water). The mixture was degirolami using vacuum/purge with nitrogen (3x). Then the suspension was heated in a flask under reflux (temperature distillation 72oC). The reaction was monitored by HPLC. 2 ml sample of the reaction mixture was filtered through Solka Flok. The filtrate (0.1 ml) was diluted in CH3CN to 10 ml and analyzed by HPLC: [25 cm phenyl column ZORBAX;acetonitrile/water containing 0.1% phosphoric acid, gradient elution from 75:25 to 90:10 CH3CN/H2O within 18 minutes, at a speed of up to 22 minutes. 90:10; flow rate 1.5 ml/min; UV detection at 200 nm].

tRdienone = 12,1 min, tR-4-Aenon = min 13,2, -5-Aenon a 14.1 min, tRexcessively recovered ketone = 14.4V min; tRethylene ether = 20,9 minutes Excessively recovered ketone should be analyzed at 192 nm.

The reaction was considered completed, to the severe, the mixture was cooled to ambient temperature. Filtration through Solka Flok removed the palladium and the filter residue was washed with ethanol (150 ml).

Download contains 51 mg/ml northward. (Note: prolonged reaction should be avoided, because it can happen redundant recovery. If the source material has slashdowns and level-5 - Aenon is more than 5% after 10 hours, then palladium should be filtered out, and the isomerization reaction is complete without the presence of a catalyst).

The solution was concentrated under reduced pressure (75 mm) approximately up to a volume of 150 ml Loading was diluted with ethanol (225 ml) and again concentrated to 150 ml.

Changing the solvent to ethanol was considered complete when the level of toluene, determined by gas chromatography, was less than 2% relative to the ethanol detected cyclohexene was not. (Note: deleting cyclohexene is important because it responds to the subsequent stage oxidative cleavage that leads to unproductive consumption periodate). 0.1 ml of sample was diluted with ethanol to 1 ml and analyzed for the content of cyclohexene (and 1,1,1-trichloroethane on the content of toluene). The conditions of the gas chromatography: [HP-5 (P>C, flow rate = 0.5 ml/min] , tRethanol = 5,6 min, tRcyclohexene = 7,7 min, tRtrichloroethane = 7,7 min, tRtoluene = 10,2 minutes the Presence of cyclohexene is also found through1H NMR (CDCl3) solution: the protons of cyclohexanone at = 5,64 frequent. per million, the proton of enonline at = 5,69 frequent. in a million.

The concentrate was diluted with hexane (250 ml) and 3N HCl (150 ml). A two-phase mixture was heated to 40oC up until ended hydrolysis ealovega ether. The layers were separated and the organic layer washed polysystem solution of sodium bicarbonate (100 ml). Hexane phase, which had a volume 291 ml and contained less than 5% of ethanol by volume, were analyzed and found that it contains 92 mg/ml northward.

The solution was concentrated under reduced pressure to 100 ml (100 mm/15oC). The download was diluted with tert-butanol (175 ml) and again concentrated to 100 ml (100 mm/40oC). Download contains 260 mg of desired 7-- matilainen/ml, the yield of 26.8 g (85%).

(Note: these connections can also be detected by gas chromatography. Application of gas chromatography for the occurrence of this reaction should be avoided, since the exact location disproportionality what about the restored Aenon = 12,8 min, tR7-alpha-epimer = 15,7 min, product = 17,3 min, tR(source) = 21,3 minutes

(See further Stage 5 at the end of the description).

A 5 l round bottom flask was loaded with deionized water (4,93 l), periodate sodium (1,55 kg) and potassium permanganate (11.1 g). For reconstitution, the suspension was mixed at 65oC for 30 minutes.

To a solution of Aenon (300 g) in tert-butanol (4,60 l) was added a solution of sodium carbonate (159 g) in water (2.3 l). A two-phase mixture was heated to 65oC. the exact location should not contain toluene, ethanol and cyclohexane. (Note: the Concentration of Aenon in the organic layer is about 56 mg ml-1). To a solution of Aenon with rapid stirring for three hours was added to the solution of periodate sodium while maintaining the reaction temperature 65oC. the Suspension was kept for 2 hours at a temperature of 65oC. Through a heated addition funnel was added a solution of periodate.

During the reaction was separated gas carbon dioxide. Slow addition provides regulated gas. While adding heat not found. While adding the formed suspension purple-brown color.

The course of the reaction was controlled by persecu water and CH3CN (1:3). The HPLC conditions [Main column UMC 25 cm x 4.6 mm, CH3CN, 0.01 M H3PO490:10, isocratic flow = 1.5 ml/min, UV detection at 200 nm]; tRof Aenon = 11.5 min, tRscaricati = 5,5 minutes

The reaction was considered complete when the contents of the source Aenon was < 0.5 mg/ml was Added water (3.0 l) and to decompose the remainder of KMnO4(the color changed from purple to brown) and the dissolution of the greater part of the solid particles deposited on the walls of the vessel, the suspension was heated in a flask under reflux for 2 hours. The resulting suspension was cooled to 15oC and filtered through dicalite (50 g). The vessel and the filter residue washed tert-butanol/water (1:2; 6.0 liters).

Filter the precipitate was analyzed for content of scaricati by dissolving 200-400 mg filter cake with 50 ml of water and 50 ml of acetonitrile and subsequent filtering in the tube through diatomaceous earth to remove minor amounts of solid orange particles of manganese. The filtrate (pH 9,0-10,5) were extracted with heptane (5.0 l).

To the water mixture was added ethyl acetate (2.6 liters) and by adding concentrated HCl (250 ml) found pH equal 2,50,3. The aqueous layer was removed.

Organice 10% of the volume. Added acetic acid (7,4 l) and the remaining ethyl acetate was removed by concentration (100 mm Hg, 60oC) content of 1% by volume. (As shown by HPLC, < 0.5% of the area). By adding acetic acid, the final volume was set equal to 5 l Removal of ethyl acetate was monitored using HPLC using the above conditions, except that the flow rate was 0.5 ml/min and UV detection was performed at 210 nm. tRethyl acetate = 7,4 min, tRacetic acid = 6,9 min Output analyte was 275 g, which corresponds to 88%. A solution of acetic acid is directly used in the next stage (education anlatma). (See further Stage 6 at the end of the description).

To a solution of scaricati in acetic acid (265 g 5.3 l) obtained at the previous stage, added BHT (5.3g) and ammonium acetate (488 g) at 20oC. the Suspension was slowly heated in a flask under reflux for 3 hours under nitrogen atmosphere. When 30oC got the solution. The internal temperature when heated in a flask with reflux condenser was 120oC. the Color changed from yellow to red and then to red-brown. The use of minor amounts ucsusa HPLC. The HPLC conditions [SB phenyl, CH3CN, 0.01 M H3PO4when the ratio of 80:20 for 30 min, flow rate = 1.5 ml/min, UV detection at 190/200 nm]. Retention time: tRanlatma = 9,4 min, tRscaricati = 5, 3 min UV detection during the reaction at 190 nm and for the source material, and analyzed product at 200 nm. The reaction was considered complete when scaricati remained less than 0.05% of the area, i.e. approximately 3-4 hours.

The reaction mixture was cooled to 60oC and after 15 min was added water (398 ml). (Note: an important addition to the acetic acid solution, the exact amount of water to 7.5% by volume).

The solution was cooled to 50oC and made a seed anlatma (1.0 g). At the 50oC crystallization occurred. The resulting suspension was passed at 50oC for 1 hour and then cooled for 2 hours to 0-2oC.

The suspension was filtered and the light tan solid was washed with a mixture of acetic acid and water at a ratio of components in the mixture 5:1 (1.0 l). Solid throughout the night was dried in vacuum at 30oC, receiving, as shown by the quantitative analysis, 255 g, 87 wt.% (balance - acetic acid) that SUP>C. the melting point of a pure substance = 175 - S, softening - 162oC.

(See further Stage 7 at the end of the description).

To 20 g of 83 weight. % anlatma added 100 ml of acetic acid, which contained 200 mg of BHT. To dissolve the suspension was heated to 60oC under a nitrogen atmosphere, then cooled to 50oC. then added 10 ml of water. The mixture is then cooled for 1.5 hours to 5oC, held for 1 hour and then filtered solid. (Note: before cooling to 5oC solution at 50oC began to crystallize). After adding BHT kg of solution was approximately 0.2 to 0.4. in/century

The mother liquor was controlled by HPLC. The HPLC conditions: [SB phenyl, CH3CN, 0.01 M H3PO4when the ratio of 80:20, for 30 minutes, flow rate 1.5 ml/min, UV detection at 200 nm]. Retention time: tRanlatma = 9,4 minutes took a sample volume of 100 μl and diluted to 10 ml with acetonitrile.

The suspension was filtered and the light tan solid was washed with a mixture of acetic acid and water at a ratio of components in the mixture 5:1 (40 ml) at 5oC. Solid during the night was dried in vacuum at 30oC, receiving as showing the HPLC, UV detection at 200 nm, the substance was 99.4% of the area.

The melting point of the MES = 112 - 115oC. the melting point of a pure substance 175 - 178oC, softening - 162oC. (see Further Stage 8 at the end of the description).

In acetic acid (1.7 l) at 20oC dissolved BHT (3.8 g). The solution was degirolami by purging with nitrogen for 30 min and one portion was added to electum (218 g, 87 wt.%). The resulting solution for 15 min was purged with nitrogen. Added 10% Pd/C (50% wet.) (38 g) and the suspension was transferred into an autoclave with a stirrer volume 1 gallon (there are 3,785 l). For washing of the suspension fed to the autoclave, used degassed acetic acid (190 mm). (Note: Before adding anlatma to acetic acid should be added BHT. The use of acetic acid, BHT stabilized, is necessary due to the instability of anlatma to oxidation).

After vacuum purging with nitrogen, the mixture was placed in a pressure vessel is 60 psi (pounds/inch2) (4,2186 g/cm2) H2and stirred at 20oC. After 10 hours of heating at a temperature of 20oC the reaction temperature was increased to 60oC to until the reaction was completed on > 99.9% uptime.

The course Rea,5 ml/min, dual UV detection at 210 and 240 nm] . Retention time: tRanlatma - 8,50 min, tRTRANS-lactam and 12.4 min, tRcolectomy - 18,4 min took a sample volume of 20 ml and diluted with acetonitrile to 2 ml.

Upon completion of the reaction (i.e., the degree of conversion of >99.9% of) the mixture was cooled to 20oC and filtered through Solka-Flok (20 g). The filter residue was washed with acetic acid (1.9 l). The filtrates were combined and concentrated at 30oC/10 mm Hg up to a volume of 570 ml was Added heptane (General 3.8 l) and the concentration was continued at atmospheric pressure (boiling point azeotrope = 91-92oC) to remove acetic acid. (Note: the Removal of acetic acid to <2% by volume is important due to the very high solubility of the product in acetic acid). Final boiling point was 98-99oC. Acetic acid was monitored at 200 nm by HPLC using a 25 cm SB phenyl column ZORBAXwhen using as eluent a mixture of CH3CN and water in a ratio of components in a mixture of 90:10, flow rate 0.5 ml/min was Selected a sample volume of 100 μl and diluted with acetonitrile to 10 ml.

The solution was concentrated to 570 ml and added MEK (2.5 liters). Azeotrope, distillates and download <5% by volume. The conditions of the gas chromatography: DB - 520 m, 0.5 ml/min helium, isotherm at 35oC; tRMEK = 6,4; tRheptane = 8,0 minutes During the removal of the heptane crystallization occurred.

Set the volume of solution equal to 600 ml and the solution for 3 hours, cooled to 20oC. the Formed suspension was kept for 2 hours at -10oC. the filter was collected solid and washed with cold MEK (150 ml). The solid was dried in vacuum at 20oC. Output - 170 g, 99%; at 210 nm product was more than 99.2% of the area. The output stage is 89%.

(See further Stage 9 at the end of the description).

Autoclave with a volume of 5 gallons (18,927 l) was loaded at room temperature with the suspension of the lactam (3.0 kg), BnMe3NCl (150 g) and potassium hydroxide on aluminum oxide (1:1, 3.0 kg) in toluene (12 l). At 20oC and slow mixing of the introduced methyl chloride (453). The suspension was heated with slow stirring to 65oC and kept for 1 hour. The temperature sensor is said to ectothermy at a temperature 52-53oC in the form of a sharp ledge.

The course of the reaction was controlled by HPLC. The HPLC conditions [SB Phenyl column ZORBAXCH3CN: 0.01 M H3PO490:10, skorosti layer was diluted with acetonitrile to volume of 2 ml. The reaction was monitored until complete conversion (>99.95 per cent). The reaction was completed at 60oC for time <60 minutes

The reaction mixture was cooled to 20oC and purged with nitrogen (4) to remove excess MeCl. The toluene solution was filtered through Solka Flok (100 g), and the vessel and the filter residue was washed with toluene (2 l). Mixed filtrates were concentrated under a pressure of 100 mm Hg and 20-30oC to a residual oil. The oil should be distributed homogeneously in heptane (10 ml/g) without the formation of turbidity.

The oil was subjected to analysis by gas chromatography on the content of toluene at a temperature of 35oC. the Product (100 ml) was dissolved in methanol (0.5 ml) and was injectively 1 ál of tRtoluene = 4,4 min, tRmethanol = 2,7 minutes

The oil was kept under vacuum until the solvent was < 2%. Oil poured into the glass stream, introduced the priming IV-a (1.25 g) and kept under vacuum (20 mm Hg) overnight.

The obtained solid is cut into chunks and grind in the mixer Waring (Waring) containing water (10 l) at a temperature of 2oC, up to the size of particles <50 μm. The suspension was filtered, washed with water (5.0 l) and dried in a stream of nitrogen overnight. Yield = 3.0 kg, 97%.

oC. To the mixture for 15 hours under nitrogen was added 90% tert-butylperoxide hydrogen (4.4 ml, 40 mmol). The HPLC analysis showed 285 g (65%) 7-ketocholesterol.

The download was filtered through Solka-Flok and the vacuum removed the solvent. The residue was dissolved in methanol and then download cooled to +5oC and kept for 30 minutes. The download was filtered and washed with cold methanol. The solid was dried in air to obtain and 2.26 g (51%) 7-ketocholesterol.

Example 3.

Getting 7-ketocholesterol (see the diagram and table in the end of the description)

In a three-neck flask with a volume of 2000 ml with air stirring added hydrate trichloride ruthenium (240 mg), 55 ml of water, cholesterylester (78,1 g) and heptane (310 ml). The speed of the air mixing paddle stirrer was 225-275 rpm.

Within 4 hours slowly added 70% tert-BuOOH (229 g). When the cooling water bath temperature was maintained equal to 15-20oC. After an induction period equal to 5-15 min, temperature load start slowly looking up the material and less than 2% of the intermediate 7-hydroxycholesterol, i.e. approximately 20-24 hours.

The course of the reaction was controlled by the main speakers UMC, a mixture of acetonitrile and water at a ratio of components in a mixture of 90:10, flow rate = 1.5 ml/min, UV detection at 200 nm. Retention time: tRcholesterolaemia = 17,0 min, tR7-ketocholesterol = 7,8 min, tRIndiana = 4.5 min, tRintermediates 7-hydroperoxides, 7-tins = 6,8, 6,9, 7,0, 8,2 minutes Later eluruumina impurities (through the 18th and 19th minutes) were 7-tert-BuOO-cholesterylester.

To the reaction mixture was added 550 ml of MEK, 390 ml of water and 39 g of sodium sulfite. The mixture was heated to 70oC up until he lost some Indiana, about 3 hours. The reaction mixture was cooled, then to remove salts of ruthenium was filtered through a pad Solka-Flok. A transparent solution was transferred into a separating funnel, separated water layer, and then the organic layer was washed with 100 ml of 1% brine. Then azeotropic distillation with heptane (after an initial concentration of 300 ml was added 800 ml of heptane) was removed MEK and tert-BuOH up until less than 0.7% of a mixture of MEK and tert-BuOH, as shown by analysis by gas chromatography.

Heptane was examined for the content of MEK and tert-BuOH gas chromatography is H = 5,3 min, tRheptane = 7,7 minutes

Set volume of 350 ml, cooled to -5oC and was filtered, washed twice with 150 ml of heptane at 0oC. After drying, the product was received, the output 62% (51,5 g, 94 wt.%, 97% of the area) in the form of not-quite-white solid.

Example 4.

Following essentially the same method described in example 1, step 1, from the corresponding starting materials of the formula 1, which is

< / BR>
and A, X and Y are defined as follows:

(a) A = 6-methylhept-2-yl, X=-CH2and Y=-OH;

(b) a = atlantal, X=-CH2and Y=ethylene glycol;

(c) A = tert-butyl di methylcellulose (TBDMS-O-), X=-CH2and Y=-OC(O)CH3and

(d) A = 6-methylhept-2-yl, X=-N(CH3) and Y=keto(=O),

received the compounds of formula (II).

In addition, cyclohexanol oxidized in cyclohexane using essentially the same methodology described in example 1, stage 1.

The source material for (b) was obtained by treatment of commercially suitable 4-androsten-3,17-dione with ethylene glycol and HCl using standard reaction conditions. Source material (C) was obtained by treatment of commercially suitable 5-androsten-3,17-diol-3-acetate TBDMS-Cl and imidazole using standard who alternova splitting commercially suitable of cholestenone (method described in example 1, stage 5) post processing and NH2CH3.

Example 5. (the diagram and table, see the end of the description).

To a solution of 16-S ether (100 g, 16-tert-butyl-salelologa ether) in hexane (500 ml) at 20oC was added water (300 ml) and the hydrate trichloride ruthenium (0,46 g). A two-phase mixture was mixed and cooled to 10oC. for 5 hours while maintaining the reaction temperature 10-15oC was added tert-BuOOH (70 wt.%) (432 g).

The reaction was slightly exothermic. To maintain the temperature between 10 and 15oC used a mixture of ice water.

After this was carried out by HPLC using SB phenyl column ZORBAX25 cm, a mixture of acetonitrile and water at a ratio of components in the mixture is from 30:70 to 80:20 for 25 min, then carried out the exposure for 15 min UV detection at 200 nm, flow rate 1.5 ml/min

Retention time: tRMin.

OTBS ether - 29,4

7-ketone - 23,8

TBHP - 3,25

The reaction was considered completed when the left <2% of the source material (<1.5 mg/ml). The typical reaction time = 10 hours. After completion of the reaction was added charcoal (10 g), then sodium sulfite (20 g) and the suspension was mixed for 30 minutes.

Sul is the allocation of a small amount of heat and the amount of additive concentration dependent residual tert-BuOOH. Using HPLC registered complete removal of tert-BuOOH. A two-phase mixture was filtered through Dicalite (sintered funnel (7.62 cm) and the filter residue was washed with hexane (300 ml). Separated water layer and the hexane layer was washed with water (100 ml x2).

The addition of acetonitrile (20 ml) were removed a small amount of the solid layer on the surface of the partition.

The hexane layer was concentrated to small volume and washed a large amount of hexane (400 ml). The solution was concentrated to a final volume of 150 ml (hexane : substrate is 2:1) and used as such at the stage of purification.

Before processing the silica-hexane solution was dried.

Treatment with silicon dioxide.

As mentioned above, the hexane solution was loaded on silicagel column (470 g, previously suspended in hexane, 60-230 mesh). To remove unreacted starting material column was suirable hexane (800 ml). Then the column was suirable 10% ethyl acetate in hexane (1000 ml), while the 7-ketone. Details column: 100 ml fractions after column was followed by TLC (thin-layer chromatography (20% ethyl acetate/hexane) or alternative HPLC (as described above).

Fracc what s the essence of the invention and to illustrate provided examples it should be understood that in practice, the invention covers all of the possible options, alterations, and modifications that are included in the scope of the subsequent claims and its equivalents.

1. The method of oxidation5-steroid alkene of General formula

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where Z is

< / BR>
or

< / BR>
And is-H; keto (=O); protected hydroxy for example, dimethyl-tert-butylsilane, trimethylsilyloxy, triethylsilane, triisopropylsilane, triphenylsilane; acetate, hydroxy; protected amino, for example, acetylamino; amino; C1- C10-alkyl, for example methyl, ethyl, 1,5-diethylhexyl, 6-methylhept-2-yl, aryl-substituted C1- C10-alkyl, for example, megafamilies, 1-(chlorophenoxy)ethyl; arylcarbamoyl1- C10-alkyl, for example 2-(4-pyridylcarbonyl)ethyl; C1- C10-alkylsulphonyl, for example, isobutylketone; arylcarbamoyl, for example, phenylcarbinol; afrosamurai1- C10-alkyl, for example, 1-methoxyethyl, 1-ethoxyethyl; Ketobemidone1- C10-alkyl, for example, 1-ketoacyl; heterothermy1- C10-alkyl, for example, omega-(4-pyridyl)butyl; carboxy; esters of carboxylic acids, for example, esters WITHalkylcarboxylic or aralkylated, such as N, N-diisopropylcarbodiimide, n-tert-butylcarbamoyl or N-(diphenylmethyl)carboxamide; carbamates, such as1- C10-allylcarbamate, especially tert-BUTYLCARBAMATE; substituted or unsubstituted derivative anilide, in which phenyl may be substituted by 1 to 2 substituents selected from ethyl, methyl, trifloromethyl or halogen (F, Cl, Br, I); urea, for example, WITH1- C10-alkylcarboxylic, such as tert-BUTYLCARBAMATE; C1- C10-alkylcarboxylic, for example, tert-BUTYLCARBAMATE; ethers, for example, n-Butylochka, atlantal; substituted and unsubstituted akrilovye esters, such as chlorphenoxy, methylphenoxy, phenyloxy, methylsulfinylphenyl, pyrimidinone;

Y is a hydroxy - group, the esterified hydroxy-group;

X - CH2-, NH-group,

in5-7-ketosteroids alkene of General formula II

< / BR>
where X, Y and a have the above values,

characterized in that5-steroid alkene of General formula I is treated with hydropredict in a solvent in the presence of a catalyst based on ruthenium.

2. The method according to p. 1, characterized in that the reaction is carried out at a temperature in the range of 5 - 132oC.

oC.

5. The method according to p. 1, characterized in that the reaction is carried out at acidic pH values.

6. The method according to p. 5, characterized in that the pH is about 1.

7. The method according to p. 1, characterized in that the reaction is carried out in an inert atmosphere.

8. The method according to p. 1, characterized in that the solvent is chosen from water, hexane, chlorobenzene, heptane or mixtures thereof.

9. The method according to p. 1, characterized in that a catalyst based on ruthenium use the catalyst on the basis of sodium tungstate-ruthenium.

10. The method according to p. 9, characterized in that the catalyst on the basis of sodium tungstate-ruthenium is RuW11O39SiNa5.

11. The method according to p. 1, characterized in that the catalyst based on ruthenium choose from RuW11O39SiNa5, RuCl3, RuCl2(PPh3)3.

12. The method according to p. 1, characterized in that hydropeaking choose from gidroperekisi tert-butyl or hydrogen peroxide.

13. The method according to p. 12, characterized in that hydropeaking is Gidropress tert-butyl.

14. The method according to p. 13, characterized in that katalizatoramisikkativami is heptane.

16. The method according to p. 1, characterized in that the5-steroid-5-7-ketosteroids alkene are respectively the formulas I and II

< / BR>
< / BR>
where Z is

< / BR>
or

< / BR>
Y is chosen from hydroxy, esterified hydroxy-group, keto and atelectasia;

X is chosen from-CH2-, -NH - or-N(CH3)-, or-N-2,4-dimethoxybenzyl;

And is any synthetically feasible substitute.

17. The method according to p. 16, characterized in that a is selected from-H, keto, protected hydroxy, acetate, hydroxy, protected amino, C1- C10-alkyl, aryl-substituted C1- C10-alkyl, amino, arylcarbamoyl1- C10-alkyl-C1- C10-alkylsulphonyl, arylcarbamoyl, afrosamurai1- C10-alkyl, closemessage1- C10-alkyl, heteroarylboronic1- C10-alkyl, complex ether carboxylic acid, carboxamide, carbamate, substituted and unsubstituted derivatives anilide, urea,1- C10-alkylcarboxylic, atelectasia, simple ester and substituted and unsubstituted kilowog ether.

18. The method according to p. 17, characterized in that

(a) a protected hydroxy-group is chosen from dimethyl-tert-BU is on the amino group is acetylamino;

(C)1- C10-alkyl selected from methyl, ethyl, 1,5-dimethylhexane, 6-methylhept-2-yl and 1-methyl-4-isopropylphenyl;

(d) aryl-substituted C1- C10-alkyl selected from omega-phenylpropyl and 1-(chlorophenoxy)ethyl;

(C) arylcarbamoyl1- C10the alkyl is 2-(4-pyridylcarbonyl)ethyl;

(f)1- C10-alkylcarboxylic is isobutylketone;

(g) arylcarbamoyl is phenylcarbinol;

(h) afrosamurai1- C10-alkyl selected from 1-methoxyethyl and 1-ethoxyethyl;

(i) Ketobemidone1- C10the alkyl is 1-ketoacyl;

(j) heteroelement1- C10the alkyl is omega(4-pyridyl)butyl;

(k) esters of carboxylic acids are esters WITH1- C10-alkylcarboxylic acids selected from carbomethoxy, carboethoxy;

(l) carboxamide selected from N, N-diisopropylcarbodiimide, N-tert-BUTYLCARBAMATE and N-(diphenylmethyl)carboxamide;

(m) carbamates selected from tert-BUTYLCARBAMATE and isopropylcarbamate;

(n) a substituted or unsubstituted derivative anilide choose from such derivatives, where phenyl may be substituted by substituents from the pet-BUTYLCARBAMATE;

(R)1- C10-alkylcarboxylic is tert-BUTYLCARBAMATE;

(q) a simple ester selected from n-Butylochka and atelectasia;

(r) substituted and unsubstituted arrowy ether selected from chlorphenoxy, methylphenoxy, phenoxy, methylsulfinylphenyl, pyrimidinone.

19. The method according to p. 16, characterized in that Z is

< / BR>
20. The method according to p. 19, characterized in that a is selected from 6-methylhept-2-yl, tert-butylcarbamoyl, phenylcarbamoyl, 2,5-dateformatsymbols, 4-methylsulfinylphenyl, isobutylketone, phenylcarbamoyl, 1-methoxyethyl, 2-(4-pyridylcarbonyl)ethyl, chlorphenoxamine and 1-ketoacyl.

21. The method according to p. 19, wherein a is 6-methylhept-2-yl.

22. The method according to p. 16, characterized in that Z is

< / BR>
23. The method according to p. 22, wherein a is phenoxy, chlorophenoxy, methylphenoxy, 2-pyrimidinone and tert-butylsilane.

24. The method according to p. 16, characterized in that the catalyst based on ruthenium catalyst is based on the sodium tungstate is ruthenium.

25. The method according to p. 24, characterized in that the catalyst on the basis of sodium tungstate-ruthenium is RuW11O39SiNa5.

27. Connection RuW11O39Na5.

28. The method of obtaining compounds of General formula

< / BR>
characterized in that the implement stage

(a) a 5-to 7-ketosteroids alkene make the connection 3'

< / BR>
(b) compound 3' is subjected to oxidation for the formation of compounds 4'

< / BR>
(c) compound 4' is subjected to hydrogenation to form a compound 5'

< / BR>
(d) compound 5' is subjected to oxidative cleavage for the formation of compound 6'

< / BR>
(e) compound 6' lactoserum for education NH-enactme 7'

< / BR>
(f) NH-enactm 7' restore for the formation of compound 8'

< / BR>
(g) compound 8' for education was identified in connection 9'



 

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