RU2663893C1 - Method for obtaining 6-dehydro-6-methylhydrocortisone or ester thereof from hydrocortisone 21-acetate - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to a process for the preparation of 6-dehydro-6-methylhydrocortisone (11β,17α,21-trihydroxy-6-methylpregna-4,6-diene-3,20-dione) or esters thereof of general formula II, in which R=COCFor H; R=COCHor H, from hydrocortisone 21-acetate of formula II, through a series of conversions comprising protection of the 11β-hydroxyl group by esterification with a trifluoroacetic acid derivative in an aprotic solvent medium under basic catalysis conditions using an effective amount of a catalyst to form 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxypregn-4-ene-3,20-dione of formula III, enol-esterification Δ-3-keto system of the obtained compound by the action of a trialkyl orthoformate in the presence of an acid catalyst to form a 3-alkoxyester Δ-3-hydroxy derivative of general formula IV, condensing it with a Mannich reagent formed in situ from formaldehyde and a secondary amine, in the presence of an acid catalyst to form a mixture of 6α- and 6β-isomers of the 6-(N-methyl-N-phenyl)-aminomethyl derivative of general formula V, cleavage of the resulting mixture of Mannich steroid bases on the C-N bond by the action of a protonic mineral acid in the presence of hydrohalic acid salts to form a 6-methylene derivative of formula VI, isomerisation of the 6-exomethylene bond to a 6,7-endomethylene bond; removal of protective groups 11β- and 21-hydroxyl groups entirely or in part; esterification of the 21-hydroxyl group with an acetic acid derivative under basic catalysis conditions.II,III,IV,V,VI.EFFECT: simple method for preparing a compound of formula I from hydrocortisone 21-acetate with output of the desired products of not less than 80 %.55 cl, 12 ex

Description

Technical field

The present invention relates to the field of organic synthesis, specifically relates to the production of steroid compounds (corticosteroids), such as 6-dehydro-6-methylhydrocortisone or its esters, and can be used in chemical and pharmaceutical industries, as well as in industrial biotechnology, for the production of steroid medical preparations.

State of the art

6-Dehydro-6-methylhydrocortisone (11β, 17α, 21-trihydroxy-6-methylpregna-4,6-diene-3,20-dione, CAS No. 85310-39-0) is an intermediate in the synthesis of 6α-methylhydrocortisone (CAS No. 1625-39-4), as well as 6α-methylprednisolone (CAS No. 83-43-2), from hydrocortisone (CAS No. 50-23-7) or 21-hydrocortisone acetate (CAS No. 50-03-3).

Obtained in accordance with the proposed method, 6-dehydro-6-methylhydrocortisone or its esters (11-trifluoroacetate 6-dehydro-6-methylhydrocortisone, 21-acetate 6-dehydro-6-methylhydrocortisone (CAS No. 22032-37-7) and 11- 6-dehydro-6-methylhydrocortisone 21-acetate trifluoroacetate) not only serve as starting substrates for further conversion to 6α-methylhydrocortisone and 6α-methylprednisolone (by chemical and combined chemical and biotechnological methods, respectively), but can also be used to produce 6-dehydro- 6-methylprednisolone (CAS No. 95810-22-3) chi chemical or biotechnological methods. In addition, 6-dehydro-6-methylhydrocortisone and its esters may be of interest as independent drugs, since it is known that, for example, 21-acetate of 6-dehydro-6-methylhydrocortisone has glucocorticoid activity three times greater than hydrocortisone. and anti-inflammatory activity superior to that of hydrocortisone more than 8 times [GB 895817, 1962].

Known methods for introducing a 6-dehydro-C ⁶ -methyl fragment with an endomethylene 6,7-double bond into the Δ ⁴ -3-keto-steroid molecule can be divided into 2 groups: 1) dehydrogenation of the corresponding 6-methyl-Δ ⁴ -3-keto -steroids and 2) catalytic isomerization of the 6-substituted ekzometilenovoy connection 6-methylene-Δ ⁴ -3-keto steroids to 6,7-endomethylenic.

Thus, in the first embodiment, the synthesis of a 6-dehydro-C ⁶ -methyl derivative from Δ ⁴ -3-keto-steroid is a process that involves first introducing a methylene group into position C ⁶ , converting it to a 6 (ξ) -methyl group, and then dehydrogenation to form a 6,7-double bond. The last stage, according to published data, is carried out using 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil) as a dehydrogenating agent [von K.-N. Bork, F. von Werder, H. Metz, K. Briickner und M. Baumgarth. Synthese eines hochwirksamen, Fluor-freien Glucocorticoid. Liebigs Ann. Chem. 747, 123-132 (1971)].

The use of chloranil in the synthesis of 6-dehydro-6-methylhydrocortisone or its 21-acetate is known.

Thus, a method for producing 21-acetate of 6-dehydro-6-methylhydrocortisone [Huang Minion, Han Kuang-Tieng, Chow Wei-Zan. The synthesis of Δ ⁶ -6-methyl-steroids. Acta Chimica Sinica, 1963, 29 (2), 99-108] of 11β, 17α-dihydroxy-6α-methylpregn-4-en-3,20-dione (compound XIII in the described method), consisting in the sequential introduction of 6.7 double bond and 21-acetoxylation of the formed 11β, 17α-dihydroxy-6-methylpregn-4,6-diene-3,20-dione (compound XIV in the described method) by C ²¹ -iodination followed by transesterification of the formed 21-I-derivative interaction with potassium acetate.

The synthesis scheme of 21-acetate 6-dehydro-6-methylhydrocortisone by a known method [Huang Minlon, Han Kuang-Tieng, Chow Wei-Zan. The synthesis of Δ ⁶ -6-methyl-steroids. Acta Chimica Sinica, 1963, 29 (2), 99-108].

For this, 1 g of compound XIII is dissolved in a mixture of 50 ml of glacial acetic acid and 50 ml of distilled ethyl acetate and chloranil is added. At the end of the reaction, the reaction mass is evaporated to dryness in vacuo, the residue is dissolved in chloroform, the unreacted chloranil is filtered off, the filtrate is concentrated, cooled, the filtrate is filtered again from the chloranil residues, the filtrate is evaporated, the oily brown residue is triturated in benzene, the solid powdery product is filtered off and washed with benzene. 0.8 g of crystals of compound XIV are obtained. Then 0.6 g of compound XIV is dissolved in a mixture of 9.5 ml of chloroform and 6 ml of methanol, 0.6 g of calcium hydroxide, 50 mg of calcium oxide and a solution of 0.55 g of iodine in 2 ml of tetrahydrofuran are added. At the end of the reaction, the precipitate is filtered off, washed with methanol, the filtrate and washing are combined, evaporated at a temperature not exceeding 30 ° C in vacuo, several ml of saturated salt solution, several crystals of sodium thiosulfate and 1 ml of 70% acetic acid are added to the resulting pale yellow oil. The yellowish precipitate is filtered off, washed with a small amount of ice water and dried over phosphorus pentoxide in a desiccator. Obtain 0.78 g of 21-iodide, which is placed in 5 ml of dimethylformamide and add 1.5 g of potassium acetate. First it is stirred at room temperature for 2 hours, then 1.5 hours at 30 ° C and then at 40-50 ° C for 4 hours. Then the reaction mixture is cooled to 5 ° C, saturated salt solution is added, the precipitate formed is filtered off, washed with ice water, dried in a desiccator over phosphorus pentoxide. The residue was dissolved in acetone, the acetone insoluble substances were filtered off, the filtrate was concentrated, the precipitate was filtered off, and 0.4 g of crystals of 6-dehydro-6-methylhydrocortisone 21-acetate were obtained, mp 132-133 ° C, after repeated recrystallization, so pl. 141-143 ° C.

Also known are a method for producing 6-methyl-11β, 17α, 21-trihydroxypregna-4,6-diene-3,20-dione or its 21-acylate [GB 895817, 1962] and a method for producing 6-methyl-11,17α-dihydroxylated 4,6-pregnadienes [US 3031476, 1962], according to the description of which (examples 1) 6,7-dehydro-6-methylhydrocortisone 21-acetate is obtained by reacting 6α-methylhydrocortisone 21-acetate with chloranil in a medium of 240 ml of tertiary amyl alcohol while boiling for 6 hours in a stream of nitrogen. At the end of the reaction, the mixture was cooled and evaporated to dryness in vacuo. The solid residue is dissolved in ~ 100 ml of ether and filtered through a paper filter from undissolved chloranil. Chloranil washed with ether on the filter. The combined ether filtrate was washed with a 2% sodium hydroxide solution and then with water until neutral, then with a saturated sodium chloride solution. The ethereal solution was dried over sodium sulfate and evaporated to dryness, the residue was crystallized from acetone. 2.65 g (66.5%) of 6-dehydro-6-methylhydrocortisone 21 acetate are obtained in the form of a solvate with acetone so pl. 133-137 ° C, the formation and structure of which is confirmed by elemental analysis and a low melting point, which remains unchanged when dried for 4 hours at a temperature of 94-100 ° C. The resulting ester is hydrolyzed with potassium hydroxide or potassium carbonate in methanol or ethanol at room temperature under a nitrogen atmosphere to form the free triol - 6-methyl-11β, 17α, 21-trihydroxy-4,6-pregnadiene-3,20-dionastll. 190-194 ° C.

A known method of producing 21-acetate of 6,7-dehydro-6-methylhydrocortisone [US 2010256105, 2010, intermediate 3] by dehydrogenation of 0.25 g of 6α-methyl precursor (intermediate 2) by reaction with chloranil (0.5 g) in a mixture of 6, 2 ml of ethyl acetate and 1.25 ml of acetic acid. The mixture, stirring on a magnetic stirrer, is degassed with nitrogen, heated to 85 ° C, then left overnight at room temperature. The mixture was filtered, the precipitate washed with ethyl acetate, the filtrate was diluted with ethyl acetate and washed with Na ₂ CO _3. The aqueous phase is extracted with ethyl acetate, the combined organic extracts washed with 1M NaOH, water and brine, dried over Na ₂ SO ₄ . The solvent was evaporated in vacuo to a greenish residue, which was dissolved in dichloromethane and the solution was evaporated to dryness to form 0.27 g of the expected product in the form of a brownish dry foam. Then, without crystallization, 0.25 g of 6,7-dehydro-6-methylhydrocortisone 21-acetate foam was dissolved in 30 ml of methanol and 6 ml of 1M NaOH was added. The reaction mass is stirred for 3 hours, acidified with 7 ml of 1M HCl, the organic solvent is removed in vacuo, the resulting residue is extracted with ethyl acetate. After washing the extract with brine, drying and evaporating in vacuo, 220 mg of 6,7-dehydro-6-methylhydrocortisone (intermediate 4) are obtained in the form of an orange foam, which is used in the subsequent synthesis without crystallization.

Another known by introducing a 6-dehydro-C ⁶ -methyl fragment endomethylenic 6,7-double bond in steroid molecule is introduced into the pre-isomerization of the C ⁶ Δ ⁴ -3-keto steroid ekzometilenovoy group. This route is most attractive, since it does not require the preliminary conversion of the 6-exomethylene group to the 6-methyl group.

Thus, it is obvious that for the introduction of the 6-dehydro-C ⁶ -methyl fragment into the hydrocortisone 21-acetate molecule, the preliminary introduction of the exomethylene group at the C ⁶ position is necessary.

, P.

and A.

den Verlauf der Umsetzung von Steroid-3,5-dienaminen mit Formaldehyd. Helv. Chim. Acta, 1973, 56(7), 2396-2404], в других же случаях енолизация проводится in situ без выделения промежуточного продукта.The introduction of the C6 methylene group is carried out by various methods using formaldehyde or its derivatives as methyleneating agents. However, all methods include the mandatory preliminary enolization of the α, β-unsaturated ketone of ring A, necessary for polarization of the double bond system with the formation of a C6 nucleophilic carbon atom, followed by the replacement of the hydrogen atom at C6 with a formyl or methylene group and differ in that in some cases intermediate 3,5-dienol is isolated as ether [D. Burn, DN Kirk and V. Petrow. Modified steroid hormones - XXXVIII. Some transfotmations of steroidal 3-alkoxy-6-formyl-3,5-dienes and related compounds. Tetrahedron, 1965, 21 (6), 1619-1624] or 3,5-dienamine [F. Schneider, A. Boiler, M.

, P.

and A.

den Verlauf der Umsetzung von Steroid-3,5-dienaminen mit Formaldehyd. Helv. Chim. Acta, 1973, 56 (7), 2396-2404], in other cases enolization is carried out in situ without isolation of the intermediate product.

The most attractive are the methods of so-called direct condensation with formaldehyde or its derivatives. This is the direct γ-methyleneation method proposed by Annen et al. [US 4322349, 1982; EP 0100874, 1984; EP 0149222, 1985; K. Annen, N. Hofmeister, N. Laurent, and R. Wiechert. A Simple Method for 6-Methylenation of 3-Oxo-Δ ⁴ -steroids. Synthesis, 1982 (1), 34-40], and the method of condensation with a Mannich reagent [R. Bohlmann et al, DE 4121484, 1993].

The direct γ-methyleneation method involves the interaction of a steroid with formaldehyde derivatives (such as dimethyl acetal, formaldehyde diethyl acetal or methoxymethyl acetate) in chlorine-containing solvents at the boiling point in the presence of an excess of phosphorus oxychloride and sodium acetate. However, this method is not suitable for the methyleneation of compounds containing an unprotected 11β-hydroxyl group. Thus, with direct γ-methyleneation of hydrocortisone 21-acetate, the yield of the 6-methylene derivative is only 18% [K. Annen, N. Hofmeister, N. Laurent, and R. Wiechert. A Simple Method for 6-Methylenation of 3-Oxo-Δ ⁴ -steroids. Synthesis, 1982 (1), 34-40, Table 1, compound 6n].

It is also known that the enolesterification of the Δ ⁴ -3-ketosystem of steroid ring A catalyzed by p-toluenesulfonic acid (p-TSC) in the presence of an unprotected 11β-hydroxyl group may be accompanied by an undesired reaction of its elimination with the formation of a Δ ^{9 (11)} bond [Q. Zhao and Z. Li. A Convenient Syntheses of 9 (11) -Dehydrosteroids from 11β-Hydroxysteroids. Synth. Commun., 1993, 23 (10), 1473-1478]. Therefore, to preserve the 11β-hydroxyl group, its protection is necessary.

It is known that in order to protect the 11β-hydroxy group, it is usually esterified to a trihaloacetate (in particular trifluoroacetate) or trimethylsilyl ether. These protections are considered the most acceptable, since they are not only easily formed, but also easily removed. The use of the method of esterification with lower acid anhydrides to protect the 11β-hydroxy group is possible, but limited due to problems arising from their subsequent removal by chemical methods of solvolysis.

Methods of using the trifluoroacetate protection of the 11β-hydroxyl group of the hydrocortisone (II) 21-acetate molecule are known. This is the method described in the patent [US 4330541, 1982, example 1], which consists in the fact that the esterification reaction of 5 g of hydrocortisone 21-acetate is carried out in pyridine by trifluoroacetic anhydride at a temperature of minus 15 ° C. Then the mixture was poured into an aqueous solution of sodium chloride, the filtered precipitate was dissolved in dichloromethane, the organic solution was washed with water, dried with sodium sulfate and evaporated to dryness. Obtain 5.1 g (82.4%) of the residue containing the 11-trifluoroacetoxy derivative (III) of 21-hydrocortisone (II) acetate. However, this compound was not characterized, since the residue containing it without purification and isolation of the crystalline product was used by the authors of the patent in the next stage of chemical synthesis.

Other patents [DE 1112511, 1961 (Example 16) and DE 1125422, 1962 (Example 15)] describe a process for the preparation of the 11-trifluoroacetoxy derivative (III) from hydrocortisone (II) 21-acetate by the action of trifluoroacetic anhydride in absolute dioxane. After 18 hours at room temperature, the reaction mixture was poured onto ice water. Then the product is extracted, the extract is washed with water, evaporated to dryness in vacuo. After crystallization of the residue in ether and chromatography on alumina, an 11-trifluoroacetoxy derivative (III) of 21-hydrocortisone (II) acetate is obtained, the yield of which is not indicated. Product characterized: mp 206-207 ° C, [α] _D + 165.7 ° (hlf); λ _max 238-240 mμ. There is no spectral characteristic.

The preparation of methyl 3,5-dienol ether of 11-trifluoroacetoxy-derivative of hydrocortisone 21-acetate - compound IVa - is not described in literature.

The preparation of ethyl 3,5-dienol ether of 11-trifluoroacetoxy derivative of hydrocortisone 21-acetate - compound IVb - is described in patents [DE 1112511, 1961 (example 16) and DE 1125422, 1962 (example 15)] and consists in the reaction of compound III with triethylorthoformate in dioxane in the presence of p-TSC at room temperature. After completion of the reaction, the mixture was poured into water and extracted with dichloromethane. The extract is washed with water, dried over sodium sulfate and evaporated to dryness. An oily residue containing compound IVb, the yield of which is not indicated, is characterized by: [α] _D ± 0 ° (hlf); λ _max 240-242 mμ, log ε 4.15. Compound IVb was not isolated in crystalline form by the authors. Spectral characteristic, absent, melting point not determined.

6-Aminomethyl derivatives of the general formula V are novel compounds not described in the literature.

The 6-methylene derivative of the 11-trifluoroacetoxy derivative of hydrocortisone 21-acetate — compound VI — is a new compound, not described in the literature.

The 6-dehydro-6-methyl derivative of the 11-trifluoroacetoxy derivative of hydrocortisone 21-acetate — compound VII — is a new compound, not described in the literature.

Compound VIII - 17α, 21-dihydroxy-11β-trifluoroacetyloxy-6-methylpregn-4,6-diene-3,20-dione (11-trifluoroacetate 6-dehydro-6-methylhydrocortisone) is a new compound, not described in the literature.

Compound IX - 21-acetoxy-11β-17α-dihydroxy-6-methylpregn-4,6-diene-3,20-dione (21-acetate 6-dehydro-6-methylhydrocortisone) is known. There is a method of obtaining a 6-dehydro-C ⁶ -methyl derivative of hydrocortisone with a protected 21-hydroxyl group, but free 11β- and 17α-hydroxyl groups, catalytic isomerization of a 6-exomethylene bond [D. Burn, JP Yardley, and V. Petrow. Modified steroid hormones - LI: Application of the Vilsmeier reaction to 11β-hydroxy steroids. Tetrahedron, 1969, 25 (5), 1155-1158], according to which 21-acetate of 6-methylene-hydrocortisone (1.75 g) in ethanol (35 ml) is boiled with stirring with 5% Pd / C (0.5 g), slowly adding 5% solution of benzyl alcohol in ethanol (10 ml). After 1 h of exposure, the completion of the reaction is determined by changing λ _max from 260 μm to 289 μm in the UV spectrum of the sample. Then the catalyst was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was crystallized from a mixture of chloroform and acetone. Get 21-acetoxy-6-methyl-4,6-pregnadiene-11β, 17α-diol-3,20-dion (1.75 g) in the form of solvated crystals with double so pl. 147 ° C (boiling) and 198 ° C. It should be noted that it is well known from the prior art that 11 (α or β) -hydroxy-pregnanes, in particular hydrocortisone derivatives, are capable of forming stable crystalline adducts (solvate complexes) with chlorinated hydrocarbons (methane or ethane derivatives), in particular with chloroform. Similar adducts (solvates) of hydrocortisone, epi-hydrocortisone and their derivatives, in which 1 mole of steroid is associated with 1 mole of solvent, are characterized by poor solubility and relatively high stability at elevated temperatures, while the destruction of the solvate containing ~ 22% chloroform is carried out by dissolving the adduct with chloroform in a solvate-forming solvent, for example methanol, and removal of chloroform by azeotropic distillation [US 2849460, 1955].

A known method of obtaining a 6-dehydro-C ⁶ -methyl derivative of hydrocortisone with protected 17α - and 21-hydroxyl groups, but free 11β-hydroxyl group [OI Fedorova, SD Shuvalova, LM Alekseeva, GS Grinenko. Method of synthesis and technology of drug manufacture. Pharmaceutical Chemistry Journal, 1982, 16 (11), 860-862] by catalytic isomerization of a 6-methylene precursor. For this, the authors heat a solution of 17α-20: 20,21-bismethylenedioxy-6-methylene-pregn-4-en-11β-ol-3-one (0.34 g) in 13 ml of glacial acetic acid to 80 ° C for 1 h in the presence of cyclohexene (0.5 ml) as a hydrogen donor and 5% palladium on charcoal (70 mg). After that, the catalyst is filtered off, the solvents are evaporated in vacuo to half the volume, ether is added to the residue, cooled and the precipitate is filtered off. 17α-20: 20,21-bismethylenedioxy-6-methyl-pregna-4,6-diene-11β-ol-3-one (185 mg, yield 54.4%) is obtained, which is further recrystallized from aqueous dioxane.

A known method for producing 6-methyl-3-oxo-delta-4,6-steroids by isomerization of the corresponding 6-methylene-pregn-4-en-3-keto compounds [US 3705181, 1972] by treatment with a strong acid, preferably aryl or alkyl -sulfonic acid, sulfuric or perchloric acid, also preferably in the presence of an acylating agent such as an anhydride or carboxylic acid chloride, according to which 17α-hydroxy-6-methylene-progesterone or its acetate is treated with acetic anhydride in the presence of p-toluenesulfonic acid in benzene in for 4-5 hours at tamper boiling point. The resulting technical product (with a yield of 46 to 88.7%) is purified by column chromatography or recrystallization. However, the description of this patent does not mention the possibility of using the known method for the synthesis of 6-dehydro-6-methylhydrocortisone or its esters. A distinctive property of this method is the concomitant acetylation of the 17α-hydroxyl group (example 1 of the method), which limits its scope.

A known method of producing medrogeston (6,17α-dimethylpregn-4,6-diene-3,20-dione) from 17α-methyl-6-methylenepregn-4-en-3,20-dione by palladium-catalyzed isomerization [US 2006178520, 2006 ]. According to the method, 17α-methyl-6-methylene-pregn-4-en-3,20-dione isomerized to medrogeston in a C _1-4 alcohol or in a mixture of such alcohols in the presence of a palladium catalyst (5% Pd / C, or 5% Al ₂ O ₃ ), at a temperature of from 60 to 95 ° C (the boiling point of the solvent) for from 30 minutes up to 1.5-3 hours. The catalyst is filtered off, washed with alcohol, the filtrate is concentrated in vacuo, the crystals are precipitated by the addition of water. After filtering, washing and drying the precipitate, medrogeston is obtained with a yield of 80.5% to 93%. However, in the description of this patent there is no example of the application of the known method for the synthesis of 6-dehydro-6-methylhydrocortisone or its esters from 6-methylene analogues.

The compound of formula 1 (6-dehydro-6-methylhydrocortisone) is known. However, the literature describes its preparation from another compound in another way [O.I. Fedorova, S.D. Shuvalova, L.M. Alekseeva, G.S. Method of synthesis and technology of drug manufacture. Grinenko. Pharmaceutical Chemistry Journal, 1982, 16 (11), 860-862], namely from 17α-20: 20,21-bismethylenedioxy-6-methylpregna-4,6-diene-11β-ol-3-one by removing the bisomethylene protection of dioxiaacetone side chain in acetic acid at a temperature of 0-11 ° C by the action of concentrated hydrochloric acid (2 ml of acetic acid and 15 ml of hydrochloric acid are used per 0.5 g of steroid). After 30 minutes, the reaction mixture was drunk on ice, the mixture was extracted with methylene chloride, the extract was washed with saturated sodium bicarbonate solution, evaporated to 1.5 ml, cooled, and the precipitate was filtered off. Get 6-dehydro-6-methylhydrocortisone with so pl. 186-187 ° C. No output specified.

Thus, the catalytic isomerization methods described above do not describe the preparation of 6-dehydro-6-methylhydrocortisone with protected 11β- and 21-hydroxyl groups and an unprotected 17α-hydroxyl group.

The closest in essence the introduction of a 6-dehydro-C ⁶ -methyl fragment into the Δ ⁴ -3-keto-pregnane molecule to the claimed method is the “Method for producing 17α-alpha-acetoxy-6-methylene-pregn-4-en-3,20-dione, medroxyprogesterone acetate and megestrol acetate ”[DE 102007026636, 2008]. According to this method, a suspension of 17α-alpha-acetoxy-pregn-4-en-3,20-dione in 2 parts of ethylene glycol dimethyl ether and 0.6 parts of triethyl orthoformate is stirred under heating, then 0.05 parts of methanesulfonic acid is added and stirred until complete conversion . After adding 0.3 parts of N-methylaniline and 4 parts of ethylene glycol dimethyl ether, 30 minutes are added. 0.23 parts of formaldehyde (about 37%). Then the reaction mixture is stirred at a temperature of at least 40 ° C. After completion of the reaction, the reaction mixture was cooled, 4.8 parts of water was added and stirred until a precipitate formed. The wet substance is separated and stirred in 2.8 parts of diisopropyl ether, filtered and washed with diisopropyl ether. The resulting 6-methyl-amino compound is suspended in 4 parts of ethylene glycol dimethyl ether and one part of concentrated hydrochloric acid is added while cooling. After complete conversion at room temperature, the solid is separated, washed with ethylene glycol dimethyl ether, and then washed with methanol. The wet substance is suspended in 1.4 parts of dimethylformamide by heating. The crystals are centrifuged at room temperature and washed with dimethylformamide and then with water. After drying, 0.83 parts of 17α-acetoxy-6-methylene-pregn-4-en-3,20-dione are obtained. Next, a suspension of 1 part of 17α-acetoxy-6-methylene-pregn-4-en-3,20-dione, 0.1 part of sodium acetate and 0.06 part of Pd / C catalyst in 10 parts of ethanol and 0.01 part 4 of methyl-1 β-cyclohexene is heated with stirring under reflux, the completeness of isomerization is determined by thin layer chromatography. Then add 1.5 parts of ethanol and filter while hot from the catalyst, which is washed with hot ethanol. The combined washings and the filtrate are concentrated to 3 parts. For complete precipitation, 7.5 parts of water are added, the crystals are separated and washed with water. After drying, 0.98 parts of megestrol acetate are obtained, which is dissolved in 12 parts of methanol with heating. The mixture is concentrated to a residual volume of 2.4 parts, cooled and centrifuged. The wet substance is dissolved in 12 parts of methanol with heating, cooled and concentrated to a residual volume of 2 parts. The solid is separated, washed with methanol and dissolved in 8 parts of acetone. After adding 0.05 parts of activated carbon is heated to a boil, activated carbon is filtered off and the filtrate is concentrated to 1 part of the residual amount. The suspension is cooled, the crystals are separated and washed with acetone. After drying, 0.85 parts of megestrol acetate are obtained. Thus, the yield in the isomerization step is 98%; and for the purified product - 85%.

However, this method does not describe the preparation of 6-dehydro-C ⁶ -methylhydrocortisone or its esters. The method described in the patent [DE 102007026636, 2008] for the preparation of a specific compound, namely megestrol acetate from 17α-hydroxyprogesterone acetate, cannot be considered as a general method for introducing a 6-dehydro-C ⁶ -methyl fragment into the Δ ⁴ -3- molecule keto steroid. The use of the method indicated in the patent for the efficient production of 6-dehydro-C ⁶ -methylhydrocortisone or its esters is not obvious, since it is well known to a specialist working in the field of organic chemistry, in particular in the field of chemistry of steroid compounds, that the applicability and effectiveness of the method is significant depend on the presence of other substituents in rings A, B, C, and D in the structure of the initial Δ ⁴ -3-keto-pregnane and their nature, for example, the presence of hydroxyl groups. The hydrocortisone molecule differs from the 17α-hydroxyprogesterone molecule by the presence of an additional two hydroxyl groups at positions C ¹¹ and C ²¹ . It should be noted that according to the description of the patent [DE 102007026636, 2008], 17α-hydroxyprogesterone was used in the synthesis, the only hydroxyl group of which is protected by the formation of an ester of acetic acid.

Disclosure of invention

The technical task in the claimed invention is to develop a simpler method for producing 6-dehydro-6-methylhydrocortisone or its esters from 21-hydrocortisone acetate while ensuring the yield of the target products of not less than 80%.

The simplification of the method is ensured by 1) by carrying out sequential functionalization reactions of the C ⁶ position of the molecule of the 11-trifluoroacetoxy derivative of 21-hydrocortisone (III) acetate with the formation of 21-acetoxy-11-trifluoroacetyloxy-6-methylene-hydrocortisone (VI) at ambient temperature ( i.e., at room temperature) without the use of heating the reaction masses; 2) by carrying out the continuous process of functionalization at C ⁶ molecules 11-trifluoroacetoxy-derivative of 21-acetate, hydrocortisone (III) without isolation of the intermediates IV and V of the expected product (VI) at key stages of the synthesis and exclusion thereby not only loss of said intermediates IV and V in the mother liquors, but also the mechanical losses that usually occur in the technological operations of extraction, filtration, drying, etc .; 3) by achieving almost complete conversion of the starting products and high selectivity of the reactions of the formation of intermediates IV and V and the target product VI during the functionalization of the C ⁶ position of the molecule of the 11-trifluoroacetoxy derivative of 21-hydrocortisone (III) acetate and thereby reducing the likelihood of side reactions ; 4) due to the almost complete elimination of the formation of by-products and the grinding of the reaction mass at the stages of catalytic isomerization and removal of the protective groups. The result is a high yield of final products I, VII, VIII and IX (from 80% to 92% or more), counting from 21-hydrocortisone (II) acetate.

The technical problem is solved by the method of obtaining 6-dehydro-6-methylhydrocortisone or its esters of General formula (I)

where R = COCF ₃ or H, R ₁ = COCH ₃ or H

from 21-hydrocortisone acetate of the formula (II),

including preliminary protection of the 11β-hydroxyl group of the hydrocortisone 21-acetate molecule by esterification with trifluoroacetic acid anhydride under basic catalysis using catalytic amounts of catalyst, followed by C ⁶ -methyleneation of the resulting 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-pregn-4-ene -3,20-dione, catalytic isomerization of the 6-exomethylene bond of the obtained 6-methylene derivative into 6,7-endomethylene with the formation of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylpregna-4,6-diene-3 , 20-dione, simultaneous, phased or sequential deprotection of 11β- and 21-hydroxyl groups by chemical solvolysis, or phased (sequential) protection of 11β, 17α, 21-trihydroxy-6-methyl-pregna-4,6-diene hydroxyl groups -3.20 dione with the formation of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylpregna-4,6-diene-3,20-dione through 21-acetoxy-11β, 17α-dihydroxy-6-methylpregna-4, 6-diene-3,20-dione.

Below is the proposed scheme for the synthesis of 6-dehydro-6-methylhydrocortisone (I) or its esters (VII, VIII and IX) from 21-hydrocortisone acetate (II).

The scheme includes 5 (for VII), or 6 (for I and VIII), or 7 (for IX) chemical reactions, which can be carried out in 3, 4, or 5 technological stages, respectively. The chemical synthesis scheme includes: 1) protection of the 11β-hydroxyl group of the hydrocortisone (II) 21-acetate molecule by the formation of the 11β-trifluoroacetyloxy derivative (III); 2) enolization of the α, β-unsaturated ketone of ring A of compound III with the formation of 3,5-dienol ether (IV); 3) a three-component condensation reaction according to the Mannich type reaction with the formation of a mixture of C ⁶ -aminomethyl derivatives (V); 4) cleavage of the aminomethyl derivatives (V) via a CN bond to form a C ⁶ -methylene derivative (VI); 5) the reaction of catalytic isomerization of a 6-exomethylene bond into a 6,7-endomethylene bond with the formation of compound VII; 6) removal of the protective groups of the molecule of compound VII completely with the formation of 6-dehydro-6-methylhydrocortisone (I) or partially with the hydroxyl group C ²¹ with the formation of compound VIII, while 6-dehydro-6-methylhydrocortisone (I) can be converted into The 21-acetoxy derivative (IX) is acetylated under basic catalysis, from which compound VII can then be obtained.

The essence of the claimed invention regarding the production of 6-dehydro-6-methylhydrocortisone or its esters is that in order to increase the yield and simplify the process, the hydrocortisone 21-acetate is first subjected to preliminary protection of the 11β-hydroxyl group, then to the methylation of the C ⁶ position, the isomerization of exomethylene groups at C ⁶ to 6,7-endomethylene, removal of the protective groups.

The advantages of the proposed method are as follows:

- trifluoroacetate protection of the 11β-hydroxyl group of hydrocortisone 21-acetate and selective deesterification of the by-product of the esterification reaction of 11,17-bis (trifluoroacetate) 21-hydrocortisone acetate with 17α-hydroxyl group regeneration is carried out in one chemical stage without isolation of the target product;

- conducting condensation with the Mannich reagent in the presence of free hydroxyl at C ¹⁷ under mild conditions (at room temperature) eliminates the appearance of undesirable products (dehydration of the 17α-hydroxy group with the formation of the Δ ¹⁶ bond and D-homo-channeling with the formation of the 6-membered ring D), which confirmed by NMR spectroscopy;

- the regioselectivity of the cleavage of the Mannich steroid base with mineral acid exclusively via the C-N bond is ensured by the presence in the reaction medium of a salt of hydrohalic acid and an alkali, or alkaline earth metal, or ammonium;

- no need to use multiple crystallization of the 11-trifluoroacetoxy derivative of 21-acetate 6-dehydro-6-methylhydrocortisone or chromatography to purify it, since the content of the main substance in the product is 90-95% (HPLC), which meets the requirements, for example, the subsequent process of introducing a 1,2-double bond (by chemical or biotechnological method) or the hydrogenation process of a 6,7-double bond to form the 11-trifluoroacetoxy derivative of 6α-methylhydrocortisone 21-acetate;

- the absence of the need to use multiple crystallization of 6-dehydro-6-methylhydrocortisone or chromatography to purify it, since the removal of the protective groups leads to a slight appearance of side compounds; the content of the main substance in the product is 90-95% (HPLC), which meets the requirements, for example, of the subsequent process of introducing a 1,2-double bond (by chemical or biotechnological method) or the hydrogenation process of a 6,7-double bond to form 6α- methyl hydrocortisone;

- reactions of trifluoroacetylation, enolesterification, condensation with Mannich’s reagent, deamination of Mannich’s steroid base are carried out at room temperature;

- a significant reduction in the losses of the main product at the stages, which is ensured by the high selectivity of chemical reactions and the possibility of combining the chemical stages into one technological process without isolation of intermediates, can significantly increase the achieved total yield of 6-dehydro-6-methylhydrocortisone or its esters (21-acetate, or 11-trifluoroacetate, or 11-trifluoroacetate-21-acetate) from hydrocortisone 21-acetate to 80.5%, or 80.0-92.17%, respectively.

The implementation of the invention

21-hydrocortisone (II) acetate, CAS No. 50-03-3, C ₂₃ H ₃₂ O ₆ (USP quality, or EP, or BP), is commercially available, can be purchased, for example, from Steraloids (USA), or from other manufacturers. 4-Dimethylaminopyridine (≥99.0%), trifluoroacetic anhydride (≥99.0%), acetic anhydride (≥99.0%), trimethylorthoformate (≥99.0%), triethylorthoformate (≥98.0%), 5-sulfosalicylic acid (≥99.0%) , p-toluenesulfonic acid (≥98.0%), N-methylaniline (≥98.0%), cyclohexene (≥99.0%), triethylamine (≥99.0%) are commercially available from Sigma-Aldrich Co. Other reagents, solvents and inert gases are commercially available, were purchased from Russian manufacturers.

To isolate products at the end of reactions by pouring the reaction masses into water, as well as to wash precipitates and extracts in organic solvents, we used drinking tap water, unless otherwise specified. Distilled water was used to prepare aqueous solutions of acids, sodium chloride, ammonia, and sodium hydroxide.

All procedures, unless otherwise specified, were carried out at room temperature or ambient temperature, that is, in the range from 20 to 25 ° C. For processes requiring lower temperatures than room temperature, cooling was provided with cold tap water (in the range of 10 to 20 ° C), or a mixture of crushed ice and cold water (in the range of 5 to 10 ° C) or a mixture of crushed ice and chloride calcium (at a temperature below 5 ° C). An electric heating mantle was used for heating during reactions at temperatures above room temperature and for evaporating the solvents at atmospheric pressure.

Labortechnik AG), при остаточном давлении 0,35±0,05 кгс/см² (35±5 кПа) и температуре воды в бане в диапазоне от 35-50°С в зависимости от природы упариваемого растворителя.Evaporation of solvents in vacuo was carried out using a Rotavapor (

Labortechnik AG), with a residual pressure of 0.35 ± 0.05 kgf / cm ² (35 ± 5 kPa) and a water temperature in the bath in the range from 35-50 ° C, depending on the nature of the evaporated solvent.

Drying of the product crystals to constant weight was carried out at a temperature of 35-45 ° C at atmospheric pressure or using a vacuum oven at a residual pressure of 0.35 ± 0.05 kgf / cm ² (35 ± 5 kPa).

A universal indicator paper with a range of values from 0 to 12 (Lahema, Czech Republic) was used to determine the pH of the washings.

Dry (anhydrous) solvents (acetone, triethylamine, methanol, ethanol) were obtained by well-known methods of organic chemistry.

Column chromatography was performed on a column (16 × 650 mm) using silica gel of the brand Silica gel 60 (0.040-0.063 mm) (Merck, Germany).

The reaction progress was monitored by thin layer chromatography (TLC) using Silica gel 60 F254 plates (Merck, Germany). UV spectroscopic determination of the end of the isomerization reaction of the 6-methylene bond of compound VI was carried out on a Cary 60 Agilent UV spectrophotometer, measuring the ratio of the optical densities of the sample solution of the reaction mixture at wavelengths D ₂₈₆ and D ₂₅₈ .

The structure and purity of all isolated compounds was confirmed by at least one of the following methods: TLC (plates for TLC Silica gel 60 F254 (Merck, Germany)), mass spectrometry, elemental analysis or nuclear magnetic resonance (NMR), high performance liquid chromatography (HPLC).

Labortechnik AG).The melting point of the isolated compounds was determined on a device to determine the melting point of M-565

Labortechnik AG).

¹ H and ¹³ C NMR spectra were determined on a Bruker Avance-400 spectrometer (Bruker BioSpin GmbH) with an operating frequency of 400 MHz and 100.6 MHz, respectively, using deuterated chloroform (99.8% D, Sigma-Aldrich), or deuterated dimethyl sulfoxide (99.9% D, Sigma-Aldrich) as a solvent relative to tetramethylsilane (TMS NMR grade ≥99.9%, Sigma-Aldrich) as an internal standard, in parts per million (ppm).

Elemental analysis was performed using a Vario MICRO Cube analyzer (Elementar Analysensysteme, GmbH).

HPLC analysis was performed on a Knauer Smartline (Germany) chromatograph equipped with a gradient HPLC pump, a cell for a thermostated column, an injector, a Smartline 2600 diode array detector, an integrator-computer, at a temperature of 24 ° C, a flow rate of 1 ml / min and UV detection at a wavelength of 254 nm. Kromasil® 100-5С18 was used as the stationary phase, and a solution of Н ₂ О in acetonitrile as a mobile phase was 35% (by volume)

The method for producing 6-dehydro-6-methylhydrocortisone or its esters of general formula (I) is carried out according to the above scheme.

21-hydrocortisone acetate (21-acetoxy-11β, 17α-dihydroxy-pregn-4-en-3,20-dione) of the formula (II),

protect the 11β-hydroxyl group by esterification with trifluoroacetic anhydride in an aprotic solvent under basic catalysis in the presence of a catalytic amount of dimethylaminopyridine. For this, 1-1.5 mol of trifluoroacetic anhydride and not more than 0.1 mol of dimethylaminopyridine are used per 1 mol of hydrocortisone 21-acetate (21-acetoxy-11β, 17α-dihydroxy-pregn-4-en-3,20-dione). Obtained with a yield of up to 99.95% of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-pregn-4-ene-3,20-dione (III), the Δ ⁴ -3-keto-system of ring A is enolitered by the action of trialkyl orthoformate in the presence of sulfaromatic (sulfosalicylic or p-TSC) as an acidic catalyst in an amount necessary for the enolization of the Δ ⁴ -3-keto group. Then, the resulting 3,5-dienol ether (IV) is subjected to catalytic condensation with a Mannich reagent formed in situ from formaldehyde and N-methylaniline, with the formation of 6- (N, N-disubstituted) -aminomethyl derivative (V), followed by deamination and conversion of the obtained 6-methylene derivative (VI) in 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylpregna-4,6-diene-3,20-dione (VII), moreover, condensation with the Mannich reagent can be carried out as with preliminary isolation, and without isolation of 3,5-dienol-ether (IV), as well as with isolation, and without dividing the condensation product (V) from the reaction mass. After this, by chemical solvolysis of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylpregna-4,6-diene-3,20-dione (VII), 6-dehydro-6-methylhydrocortisone (I) or its 11β-trifluoroacetate is obtained (Viii). In this case, the removal of the protective groups of compound VII with the formation of compound I can be realized simultaneously under the conditions of the main catalysis or stepwise through the formation of compound VIII by solvolysis under conditions of acid catalysis and subsequent solvolysis of the 11-trifluoroacetoxy group of compound VIII. The synthesis of 21-acetoxy-11β, 17α-dihydroxy-6-methylpregna-4,6-diene-3,20-dione (IX) can be accomplished by selective acetylation of the 21-hydroxyl group of compound I or by selective removal of the trifluoroacetyl group of compound VII under known conditions [US 4330541, 1982, example 1].

The total attainable yield of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylpregna-4,6-diene-3,20-dione (VII) from hydrocortisone (II) 21-acetate is 92.17%.

The total achieved yield of 6-dehydro-6-methylhydrocortisone (VIII) 11-trifluoroacetate from hydrocortisone (II) 21-acetate is 82.94%.

The total achieved yield of 6-dehydro-6-methylhydrocortisone (I) from hydrocortisone (II) 21-acetate is 80.5%.

The total attainable yield of 6-dehydro-6-methylhydrocortisone (IX) 21-acetate from hydrocortisone (II) 21-acetate is 80.0%.

The protection of the 11β-hydroxyl group of the hydrocortisone (II) 21-acetate molecule is carried out by the formation of trifluoroacetic acid ester in an organic solvent under basic catalysis. This protection option is most optimal, since the esterification reaction proceeds under mild conditions with an almost quantitative yield. In addition, the trifluoroacetate protecting group, stable in an acidic environment, is easily removed if necessary by hydrolysis under the conditions of basic catalysis. Acylation is carried out using the minimum required amount of trifluoroacetic anhydride (TFA) under anhydrous conditions in an organic aprotic solvent. One skilled in the art of organic chemistry, as well as the prior art, knows that instead of trifluoroacetic acid anhydride, trifluoroacetic acid chloride can be used in this process, acetic acid chloride can be used in this process instead of acetic anhydride, and as an aprotic solvent, inventions - a method for producing 6-dehydro-6-methylhydrocortisone or its esters - any aprotic (non-polar, low-polar and polar) solvents can be used, data for carrying out the reaction and inert with respect to the acylating reagent and catalyst, such as dialkyl ketones (e.g. acetone, methyl ethyl ketone), cyclic ethers (e.g. dioxane, tetrahydrofuran) and others known in the art to ensure the completeness of the reaction. As the main catalyst, heteroaryl compounds (e.g., pyridine or its derivatives), or alkylamines (e.g., triethylamine), or other organic bases, or mixtures thereof, commonly used to catalyze acylation reactions of hydroxyl groups known in the art, can be used. The most optimal temperature regime from a technological point of view is the process of esterification at ambient temperature. The duration of the process is determined by the results of monitoring the content of the starting product in the reaction mass. The minimum amount of catalyst required to ensure a complete and fast esterification reaction is determined experimentally and may vary depending on the catalyst used.

The trifluoroacetylation reaction of compound II proceeds regionally, preferably esterifying the secondary hydroxyl group at the C ¹¹ atom of compound II. To ensure the progress of the reaction, the necessary minimum amount of trifluoroacetic anhydride is 1 mol per 1 mol of steroid. For a more complete and quick reaction, a small excess of the acylating agent is used (~ 1.2-1.5 mol of TFA per 1 mol of steroid). However, this condition is not required. The use of an excess amount of the reagent leads to partial trifluoroacetylation of the tertiary hydroxyl group at C ¹⁷ of reaction product III with the formation of 10-20% impurities of 11β, 17α-dithrifluoroacetyloxy derivative (IIIa).

However, under the conditions of our method, the C ¹⁷ trifluoroacetic acid ester is removed easily and selectively with the regeneration of the 17α-hydroxyl group and the trifluoroacetate protection of the 11β-hydroxyl group, which is achieved by treating the reaction mass with triethylamine (TEA) in the minimum required amount. The yield of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-pregn-4-en-3,20-dione (III) in the step is from 96 to 99.95%.

Synthesis of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylene-pregn-4-ene-3,20-dione (VI) from 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-pregn-4-en-3, 20-dione (III) includes three sequential chemical processes that can be carried out with the isolation of any of the intermediates of the general formulas IV and V or without isolation according to the following variants of the chemical synthesis scheme:

Variant of scheme 1: III - IV - V - VI; or

Variant of scheme 2: III - IV - [V] - VI; or

Variant of scheme 3: III - [IV] - V - VI; or

Variant of scheme 4: III - [IV] - [V] - VI.

The most optimal and preferred option is scheme 4.

To increase the nucleophilicity atom C ^6, and thereby reduce the likelihood of side condensation processes on other reaction centers (e.g., at C ²⁾ in the first synthesis step is conducted enolization reaction of Δ ⁴ -3-ketosistemy ring A of the compound III to form 3,5- dienol ether of General formula IV. The enolesterification reaction of the Δ ⁴ -3-ketosystem of ring A, both with the release of enol ether IV (options 1 and 2), and without isolation of enol ether IV (options 3 and 4) from the reaction mixture, can be carried out with or without the use of a solvent. The enolesterification reaction of the Δ ⁴ -3-ketosystem with a solvent is carried out by the action of formic acid trialkyl orthoester (e.g., trimethyl orthoformate or triethyl orthoformate) using the minimum amount of tri-alkyl orthoformate necessary to ensure the reaction (at least 1 mol per 1 mol of steroid). For a more complete and quick reaction (15-30 minutes, but not more than 2 hours), an excess of trialkyl orthoformate is used (from 2.5 to 9 mol per 1 mol of steroid). However, this condition is not required. The reaction is carried out under anhydrous conditions in an appropriate protic solvent — an aliphatic alcohol (in methanol or ethanol) or in an aprotic solvent selected from the group of cyclic ethers (for example, dioxane or tetrahydrofuran) or aromatic hydrocarbons of the benzene group (for example, benzene or toluene). The enolesterification reaction of the Δ ⁴ -3-ketosystem without the use of a solvent is carried out in a trialkyl orthoformate reagent medium.

As the enolization catalyst, there can be any protic acid that provides the enolization of the Δ ⁴ -3-keto ring system of ring A of compound III to form 3,5-dienol, known to the person skilled in the art, in particular organic and mineral acids. Mineral acids are selected from the group of water-soluble oxygen-containing (for example, HClO ₄ , H ₂ SO ₄ , HNO ₃ ) or oxygen-free (for example, HCl). It is preferable to use organic acids, for example sulfoaromatic (sulfosalicylic acid, p-TSC or the like), both anhydrous and in the form of crystalline hydrate. When carrying out the reaction without isolating enol ether IV (option 3 and 4) from the reaction mixture, it is preferable to use p-TSC, which is also a catalyst for the subsequent aminomethylation reaction.

In the synthesis of compounds of general formula V, the introduction of the substituent at position C ^{6 is} carried out by the method of three-component condensation according to the Mannich reaction using a Mannich reagent formed in situ by the interaction of formaldehyde and N-methylaniline or other secondary amines, suitable for the formation of 6- (N, N-disubstituted) -aminomethyl compounds and known in the art, for example, N-ethylaniline, diphenylamine, N-methyl-n-toluidine and the like. [GB 1280570, 1972].

According to the present invention, the Mannich reaction with the formation of compounds of general formula V can be carried out both with the isolation of product IV from the reaction mass (options 1 and 3), and without isolation (options 2 and 4). It should be noted that the condensation of a compound of general formula IV with a reagent obtained from formaldehyde and a secondary amine to form compounds of general formula V, performed both without isolation of compound IV from the reaction mass and with isolation, can be carried out in a mixture of trialkyl orthoformate and the corresponding aliphatic alcohol. In this case, in the first case, the ratio of trialkyl orthoformate and alcohol is determined by the conditions for the enolesterification reaction, as mentioned above, and in the second case, aliphatic alcohol is used to dissolve the p-TSC catalyst, and can also be used as a diluent for the reaction mass to ensure its mobility. However, it is preferable to carry out the Mannich reaction without isolating enol ether IV (options 3 and 4) in a trialkyl orthoformate medium without using solvents both at the enol ether preparation stage and at the aminomethylation stage. Both processes are carried out at room temperature. At the end of the reaction to obtain enolether IV, N-methylaniline and a 30-40% aqueous formaldehyde solution are added to the reaction mass.

The aminomethylation reaction is non-stereoselective: a mixture of 6α- and 6β-diastereomeric Mannich steroid bases (Va and Vb, respectively) is formed. The aminomethylation reaction can be carried out in a medium containing a cyclic ether (for example, dioxane or tetrahydrofuran) or an aromatic hydrocarbon of the benzene group (for example, benzene or toluene), and these solvents or mixtures thereof can be added to the reaction mass containing compounds of the general formula V after completion of the aminomethylation reaction. A solution of a compound of general formula V in an aromatic hydrocarbon is washed with 1-5% aqueous ammonia to remove p-TSC and then with water. This solution in an aromatic hydrocarbon can be used in the next deamination step without extracting a mixture of isomers of the general formula V (options 2 and 4) or the specified mixture of Mannich’s isomeric steroid bases can be extracted from the solution (options 1 and 3). However, the latter is impractical, since both isomers can be subjected to a subsequent deamination reaction with the formation of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylene-pregn-4-ene-3,20-dione (VI) without isolation and separation.

The region-directed cleavage of the Mannich steroid base of general formula V via CN is carried out by the action of mineral acids, for example, 30-35% hydrochloric acid or 50-70% sulfuric acid (preferably 55-60% sulfuric acid) in an aromatic hydrocarbon of a series of benzene (toluene or benzene) with the addition of an aprotic solvent miscible with water, for example, dialkyl ketone (acetone or methyl ethyl ketone) or cyclic ether (dioxane or tetrahydrofuran). The addition of a proton solvent, in particular, a lower aliphatic alcohol (methyl or ethyl alcohol, or others) can lead, firstly, to a partial cleavage of the Mannich steroid base of general formula V via CC bond with the regeneration of starting compound III, and secondly, the lifting (removing) the ester group at C ²¹ formed at both side product III, and at the desired product VI. The regionally directed cleavage reaction of the Mannich steroid base of general formula V via CN bond can be carried out in the presence of mineral salts, for example, alkali or alkaline earth metal halides, or ammonium halides. As the acid forming metal salts, hydrochloric or hydrobromic or hydrofluoric acids can be used. As the alkali metals that form the salts of hydrohalic acids, elements of the 1st group of the periodic system of chemical elements (tables of D.I. Mendeleev) can be used - lithium, sodium, potassium. As alkaline earth metals, forming salts of hydrohalic acids, elements of the 2nd group of the periodic system of chemical elements — calcium, barium, and magnesium — can be used.

To carry out the deamination reaction without isolating the mixture of Va and Vb isomers (options 2 and 4), the solution of the Mannich (V) steroid base mixture in aromatic hydrocarbon is diluted with the minimum amount of dialkyl ketone (at least 40% vol.), 55-60% sulfuric acid solution is added and mineral salt. The reaction is carried out at room temperature. At the end of the reaction, the reaction solution is washed from acid in a separatory funnel, first with water to a pH of ~ 6-7, then with 5% aqueous ammonia and then with water until neutral. The solvent was evaporated in vacuo or at atmospheric pressure. The remainder of the aromatic hydrocarbon can be removed by azeotropic distillation with any convenient solvent, forming an azeotropic mixture with an aromatic hydrocarbon and miscible with water, for example, ethyl or methyl alcohol. Crystallization of the reaction product is carried out by dissolving the residue after distillation in alcohol (ethyl or methyl) and diluting the resulting solution with water. The crystals are filtered off.

The achieved yield of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylenepregn-4-en-3,20-dione (VI) from hydrocortisone (II) 21-acetate is:

according to option 1 (II - III - IV - V - VI) - from 87.7 to 91.8%;

according to option 2 (II - III - IV - [V] - VI) - from 88.3 to 92.5%;

according to option 3 (II - III - [IV] - V - VI) - up to 93.8%;

according to option 4 (II - III - [IV] - [V] - VI) - up to 97.8%.

It should be noted that the deamination reaction in an organic solvent or solvent mixture by the action of a mineral acid (sulfuric or hydrochloric) without the addition of an inorganic salt is non-selective: along with deamination, a deaminomethylation process takes place with the regeneration of compound III. The use of inorganic salts in combination with mineral acid is not obvious, it is not known from the prior art, to ensure the regional directionality of the splitting of steroid Mannich bases on the C-N bond has not been previously used. The reaction without the addition of an inorganic salt leads to a decrease in the yield of the product. Conducting the reaction by the action of concentrated hydrochloric acid in tetrahydrofuran and ethanol (a literary version of the splitting of Mannich base [RU 2297423, 2007]), although it leads to a reduction in the duration of the process, this yields product VI, which is not suitable for the subsequent isomerization reaction to form compound VII without further purification, for example, crystallization. As a result of purification by crystallization, the yield at the stage of synthesis of compound VI is only 60-65%.

To obtain 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylpregna-4,6-diene-3,20-dione (VII), polar solvents such as lower carboxylic acids (e.g., acetic acid) can be used as the medium acid) and aliphatic alcohols (e.g. methanol, ethanol).

The catalytic isomerization of the exomethylene double bond of compound VI into the endomethylene 6,7-double bond of compound VII in the present invention is carried out in the presence of conventionally used catalysts, for example palladium adsorbed on carbon (palladium catalyst) and others known in the art. The reaction is carried out at the boiling point of the reaction mixture. The process is controlled by determining the composition of the reaction mass by absorption in the UV spectrum at wavelengths corresponding to the absorption maxima of compound VI (at 239 nm) and compound VII (at 286 nm). At the end of the isomerization process, the catalyst is filtered off from the hot reaction mass. The reaction product is isolated by diluting the residue after distilling off the solvent with water. The yield of the 11-trifluoroacetoxy derivative of 6-dehydro-6-methylhydrocortisone (VII) 21-acetate in the step is 94-96%.

The removal of ester groups at C ¹¹ and C ^{21 of} compound VII can be carried out simultaneously or in stages by solvolysis reactions.

It is well known in the art that to remove the protective ester groups by solvolysis, an alkali metal hydroxide solution can be used either in water or in the corresponding aliphatic alcohol (for example, methanol) with a base concentration of from 1 to 20%. Complete removal of the ester groups at C ¹¹ and C ²¹ to form compound I is carried out by reaction of solvolysis catalyzed by a strong base. The reaction is carried out in methanol. As a strong base, a catalytic amount of alkali metal hydroxide (sodium or potassium) is used in the form of a 10% aqueous solution. Get 6-dehydro-6-methylhydrocortisone (I) with a basic substance content of 90-95%. The product can be used in the chemical or biotechnological process of 1,2-dehydrogenation, in the chemical process of hydrogenation of 6,7-double bonds, as well as in the synthesis of 21-esters, without further purification.

The removal of the ester group at C ²¹ of compound VII with the preservation of the 11β-trifluoroacetyloxy group and the formation of 6-dehydro-6-methyl-hydrocortisone (VIII) 11-trifluoroacetate is carried out under conditions of acid catalysis.

Removal of the trifluoroacetyl group at C ¹¹ of compound VII while maintaining the 21-acetoxy group and the formation of 6-dehydro-6-methylhydrocortisone (IX) 21-acetate can be carried out in a medium containing an aliphatic C _1-4 alcohol under basic catalysis, for example , the action of triethylamine in methanol under the conditions of the patent [US 4330541, 1982, example 1].

It should be noted that the synthesis of compound VII may be, in turn, implemented consistent from compound I by acylation of the hydroxyl groups at C ¹¹ and C ^21.

Esters of 6-Dehydro-6-metilgidrokortizona general formula I may be prepared by any known art method, in stages performing the esterification of the hydroxyl groups initially atsetiliruya hydroxyl group at C ^{June 21-dehydro-6-metilgidrokortizona} (general formula I, wherein R = R ₁ = H) with the formation of 6-dehydro-6-methylhydrocortisone 21-acetate (general formula I, where R = Н; R ₁ = ССОН ₃ ), and then trifluoroacetylating the hydroxyl group at the C ¹¹ atom of 6-dehydro-6 21-acetate -methylhydrocortisone with the formation of 11-trifluoroacetyloxy-derivative 21-acetate 6-dehydro-6-methi hydrocortisone (general formula I, wherein R = COCF _3; R ₁ = COCH _3). The specialist in the field of chemistry of steroid compounds knows that acetylation of the primary hydroxyl group at the C ²¹ atom of the hydrocortisone derivative to form the 21-acetate of the hydrocortisone derivative can be realized only in the first place under the conditions of basic catalysis by the well-known method of acylation of the primary hydroxyl group, namely, the interaction with acetylating agent - anhydride or acetic acid chloride. In this case, ammonia derivatives — heteroaryl compounds (for example, pyridine), or alkylamines (for example triethylamine), or any other organic bases suitable for this purpose and known from the prior art can be used as a catalyst. In this case, trifluoroacetylation of the secondary hydroxyl group at the C ¹¹ atom of the 21-acetylated hydrocortisone derivative is carried out only in the second place and can be carried out under the conditions of basic catalysis by the action of trifluoroacetic anhydride or acid chloride, and ammonia derivatives - heteroaryl compounds can be used as a catalyst (for example, dimethylaminopyridine) or alkylamines (e.g. triethylamine).

Thus, the synthesis of compound IX from compound I can be carried out by acetylation under basic catalysis. The reaction can be carried out in an organic base medium (for example, pyridine), or in an aprotic solvent or a mixture of aprotic solvents, which may be used dialkyl ketones, cyclic ethers, aromatic hydrocarbons, organochlorine derivatives of methane or ethane (chloroform, dichloromethane, carbon tetrachloride, dichloroethane and the like).

The synthesis of compound VII from compound IX can, in turn, be carried out by trifluoroacetylation of a hydroxyl group at C ¹¹ under the conditions of obtaining compound III from 21-hydrocortisone (II) acetate of the present invention.

The claimed invention is illustrated by the following examples. The duration of the reactions is for illustration only. Product yields are for illustrative purposes only. The use of inorganic salts is for illustration purposes only. Instead of these salts, any water-soluble salts formed by hydrohalic acids, for example, chlorides and bromides of lithium, sodium, potassium, magnesium, barium, ammonium and others, can be used without loss of effectiveness.

Example 1. Obtaining 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy pregn-4-en-3,20-dione (III)

Option 1

To a suspension of 10 g (24.722 mmol) of 21 hydrocortisone (II) acetate in 80 ml of dry acetone was added 0.3 g (2.455 mmol) of dimethylaminopyridine. Then, at a temperature not exceeding 10 ° C., 4.2 ml (6.28 g, 29.9 mmol) of trifluoroacetic anhydride were added. The reaction mass was warmed to room temperature (20-25 ° C) and stirred for 1.5 hours. At the end of the reaction, 10 ml (7.28 g, 71.94 mmol) of dry triethylamine were added, kept for 15 minutes. Then 4.7 ml (4.93 g, 82.1 mmol) of acetic acid were added dropwise to a pH of 6 and the reaction mass was slowly poured into 240 ml of water at a temperature of 8-10 ° C. The suspension was kept under vigorous stirring for 1 h at the same temperature. The precipitate was filtered off, washed with water to pH ~ 7 wash water, dried to constant weight. Received 11.88 g (23.736 mmol) of compound III with a yield of 96.01%. Mp. 204-206 ° C (lit. 206-207 ° C [DE 1125422, 1962]). ¹ H NMR (400 MHz, CDCl ₃ , δ, ppm): 5.70 (1H, s, H-4), 5.67 (1H, m, H-11), 5.09 (1H, d, J = 17.4 Hz , Н-21), 4.67 (1Н, d, J = 17.4 Hz, Н-21), 2.14 (3Н, s, СН ₃ С (O)), 1.26 (3Н, s, Н-19), 0.80 (3Н , s, H-18); ¹³ C NMR (100.6 MHz, CDCl ₃ , δ, ppm): 204.9, 198.8, 170.5, 170.1, 122.9, 89.1, 75.4, 67.6, 54.9, 51.4, 47.0, 38.5, 35.5, 35.4, 34.5, 33.5, 32.2, 31.8, 31.7, 23.5, 20.6, 20.5, 16.4. Found: C 60.47%; H, 6.24%; C ₂₅ H ₃₁ F ₃ O ₇ . Calculated: C 59.99%; H 6.24%.

Option 2

The reaction mixture, consisting of 100 g (247.22 mmol) of hydrocortisone 21-acetate, 500 ml of tetrahydrofuran and 10 g (81.833 mmol) of dimethylaminopyridine, was cooled with stirring to a temperature of 3-5 ° C. Then, 42 ml (62.79 g, 298.96 mmol) of trifluoroacetic anhydride were slowly added to the reaction mixture in a stream of dry nitrogen so that the temperature of the reaction mixture did not exceed 7-8 ° C. After that, the bath with the cooling mixture was removed. The reaction mass was stirred until the temperature in the mass rose to room temperature (self-heating). At the end of the exposure, the reaction mass was heated to boiling point and tetrahydrofuran was distilled off at atmospheric pressure until the temperature in vapors reached 70 ° С.

The bath for heating was changed to a bath for cooling. The bottoms suspension was cooled to a temperature of 10 ° C and 55 ml (40.04 g, 395.69 mmol) of triethylamine were added via a dropping funnel to a pH of 8-9. After that, the cooling bath was removed, the suspension was stirred at room temperature for 1 h.

Upon completion of the reaction, the reaction mass was poured with vigorous stirring into 600 ml of water, cooled to a temperature of 0-2 ° C. Stirred at the same temperature for 10-15 minutes. and 11 ml (11.54 g, 192.17 mmol) of acetic acid was added to neutralize triethylamine. The suspension was stirred at a temperature of 20-25 ° C for 20 minutes. The precipitate was filtered and washed on the filter with water to a pH of ~ 7 wash water, dried to constant weight. 123.67 g (247.09 mmol) of compound III were obtained in a yield of 99.95%.

Option 3

The esterification reaction was carried out similarly to option 1, using dimethyl sulfoxide as the aprotic solvent. From 1 g (2.472 mmol) of 21 hydrocortisone (II) acetate, 1.12 g (2.238 mmol) of compound III were obtained in a yield of 90.53%.

A. Scheme, option 1: III - IV - V - VI

Example 2. Obtaining 3-methoxy-21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-pregn-3,5-dien-20-one (IVa, R = CH ₃ )

Option 1

To a suspension of 5 g (9.99 mmol) of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-pregn-4-ene-3,20-dione (III) in a mixture of 20 ml of dry methanol and 10 ml (9.676 g, 91 , 18 mmol) of trimethylorthoformate was added 0.125 g (0.726 mmol) of anhydrous p-TSC. The reaction mass was stirred for 30 minutes at room temperature. The excess p-TSC was neutralized with triethylamine, poured into 200 ml of ice water, the suspension was cooled to 0-2 ° C and kept under stirring for 2 hours. The precipitate was filtered off, washed on the filter with water to pH ~ 7 washing water and a minimum amount of methanol, dried to constant weight. Received 5.04 g (9.795 mmol) of compound IVa in the form of white crystals with a yield of 98.05%. Mp 177 ° C (decomp.). ¹ H NMR (400 MHz, CDCl ₃ , δ, ppm): 5.72 (1H, s, H-11), 5.15-5.09 (3H, m, H-4, H-6 and H-21), 4.68 (1Н, d, J = 17.4 Hz, Н-21), 3.57 (3Н, s, СН ₃ О), 2.16 (3Н, s, СН ₃ С (O)), 1.03 (3Н, s, Н-19 ), 0.80 (3H, s, H-18); ¹³ C NMR (100.6 MHz, CDCl ₃ , δ, ppm): 205.0, 170.6, 155.4, 141.1, 121.0, 116.7, 97.5, 89.3, 75.8, 67.6, 54.3, 52.6, 50.6, 47.0, 38.7, 35.5, 34.6, 33.6, 31.4, 28.4, 24.8, 23.5, 21.1, 20.5, 16.3.

Option 2

To a suspension of 1 g (1.998 mmol) of compound III in a mixture of 4.7 ml of dry methanol and 0.55 ml (0.532 g, 5.015 mmol) of trimethylorthoformate was added 0.011 g (0.05 mmol) of anhydrous sulfosalicylic acid (CCK). The reaction mass was stirred for 2 hours at room temperature. Excess CCK was neutralized with triethylamine. The reaction mass was diluted with ice water 3 times and kept with stirring for 30 minutes. at a temperature of 8-10 ° C. The precipitate was filtered off, washed on the filter with water to a pH of ~ 7 wash water and a minimum amount of methanol, dried to constant weight. 0.96 g (1.816 mmol) of compound IVa were obtained in a yield of 90.89%.

Example 3. Obtaining 3-ethoxy-21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxypregn-3,5-dien-20-one (IVb, R = CH ₂ CH ₃ )

Under the conditions of obtaining compound IVa (option 1), 20 ml of anhydrous ethanol and 10 ml (8.91 g, 60.121 mmol) of triethylorthoformate were used, from 5 g (9.99 mmol) of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy 4-en-3,20-dione (III) gave 4.94 g (9.346 mmol) of compound IVb in 93.55% yield. Mp 160 ° C (decomp.). ¹ H NMR (400 MHz, CDCl _3, δ, ppm): 5.72 (1H, s, H-11), 5.17-5.07 (3H, m, H-4, H-6 and H-21), 4.68 (1H, d, J = 17.4 Hz, H-21), 3.76 (2H, q, J = 7.0 Hz, CH ₂ O), 2.16 (3H, s, CH ₃ C (O)), 1.28 (3H, t, J = 7.0 Hz, CH ₃ CH ₂ O), 1.03 (3H, s, H-19), 0.80 (3H, s, H-18); ¹³ C NMR (100.6 MHz, CDCl ₃ , δ, ppm): 205.0, 170.6, 154.5, 141.3, 116.4, 98.0, 89.3, 75.8, 67.6, 62.2, 59.5, 52.6, 50.6, 47.0, 35.5, 34.8, 33.6, 31.4, 28.4, 25.0, 23.5, 21.1, 20.5, 16.3, 14.6.

Example 4. Obtaining 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6ξ- (N-methyl-N-phenylaminomethyl) pregn-4-en-20-one (V)

To a suspension of 10 mmol of 3,5-dienol ether (IVa or IVb) in 15 ml of absolute alcohol (methanol or ethanol, respectively), 2.15 ml (2.122 g, 19.8 mmol) of N-methylaniline was added. Then, with stirring, a solution of 0.125 g (0.725 mmol) of p-TSC in 1.25 ml of the corresponding alcohol and 2 ml (2.18 g, 0.807 g in 100%, 26.86 mmol) of a 37% aqueous solution was added dropwise. formaldehyde. The reaction mass was stirred at 20 ° C for 2 hours. At the end of the reaction, the reaction mass was diluted with 20 ml of the corresponding alcohol and poured slowly with vigorous stirring into 110 ml of water. The precipitate was filtered off, washed with water to pH ~ 7 wash water, dried to constant weight. Compound V (mixture of isomers) was obtained in quantitative yield. Without purification and separation of the epimers used in the next stage. To obtain an analytically pure sample method used to column chromatography on SiO ₂ pretreated with triethylamine.

Mp = 112-117 ° C.

6α-Isomer (Va), ¹ H NMR (400 MHz, CDCl ₃ , δ, ppm): 7.28-7.22 (2H, m, H-3,5 (NPh)), 6.79-6.69 (3H, m , H-2,4,6 (NPh)), 5.87 (1H, s, H-4), 5.70 (1H, m, H-11), 5.08 (1H, d, J = 17.4 Hz, H-21) , 4.66 (1H, d, J = 17.4 Hz, H-21), 3.70 (1H, dd, J = 3.1, 14.5 Hz, NCH ₂ ), 3.14 (1H, dd, J = 10.4, 14.5 Hz, NCH ₂ ) 2.97 (3H, s, NCH ₃ ), 2.16 (3H, s, CH ₃ C (O)), 1.19 (3H, s, H-19), 0.80 (3H, s, H-18).

6β-Isomer (Vb), ¹ H NMR (400 MHz, CDCl ₃ , δ, ppm): 7.28-7.22 (2H, m, H-3,5 (NPh)), 6.79-6.69 (3H, m , H-2,4,6 (NPh)), 5.83 (1H, s, H-4), 5.70 (1H, m, H-11), 5.07 (1H, d, J = 17.4 Hz, H-21) , 4.69 (1H, d, J = 17.4 Hz, H-21), 3.76 (1H, dd, J = 10.8, 14.5 Hz, NCH ₂ ), 3.32 (1H, dd, J = 4.1, 14.5 Hz, NCH ₂ ) , 3.02 (3H, s, NCH _3), 2.16 (3H, s, CH ₃ C (O)), 1.36 (3H, s, H-19), 0.83 (3H, s, H-18); ¹³ C NMR (100.6 MHz, CDCl ₃ , δ, ppm): 204.8, 198.7, 170.6, 170.2, 148.5, 129.4, 125.4, 116.8, 112.3, 89.1, 75.1, 67.6, 57.2, 54.7, 51.3, 46.8, 42.3, 39.7, 38.1, 37.8, 35.5, 34.5, 33.6, 33.3, 27.9, 23.3, 22.8, 20.5, 16.4. Found: C 64.08%; H 6.52%, N 2.15%, C ₃₃ H ₄₀ F ₃ NO ₇ . Calculated: C 63.96%; H, 6.51%; N, 2.26%.

Example 5. Obtaining 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylene-pregn-4-en-3,20-dione (VI)

Option 1

To a suspension of 2.5 g (4.034 mmol) of a mixture of 6α and 6β isomers of compound V in a mixture of 30 ml of toluene and 15 ml of methyl ethyl ketone was added 1 g (11.515 mmol) of lithium bromide and 2 ml (3 g, 1.798 g in 100%, 18.332 mmol) 60% sulfuric acid.

The reaction mass was kept at room temperature for 1 h and transferred to a separatory funnel. The acidic layer was separated, extracted with toluene, and the extract was combined with the organic layer. The toluene solution was washed with 60% sulfuric acid, water to a pH of 6-7, 5% aqueous ammonia and water until neutral. Then the solution was clarified with activated carbon and evaporated, removing the remaining toluene with methanol. The bottom residue was poured into 70 ml of water, the suspension was kept at a temperature of 8-10 ° C, the precipitate was filtered. 1.94 g (3.785 mmol) of compound VI were obtained with a yield of 93.83%. Mp 191-193 ° C. ¹ H NMR (400 MHz, CDCl ₃ , δ, ppm): 5.86 (1H, s, H-4), 5.68 (1H, m, H-11), 5.09-5.01 (3H, m, CH ₂ = and H-21), 4.69 d (1H, d, J = 17.4 Hz, H-21), 2.15 (3H, s, CH ₃ C (O)), 1.18 (3H, s, H-19), 0.80 (3H, s, H-18); ¹³ C NMR (100.6 MHz, CDCl ₃ , δ, ppm): 204.9, 199.2, 170.6, 168.2, 144.1, 120.6, 115.4, 89.0, 75.4, 67.6, 53.7, 51.7, 46.9, 39.7, 38.7, 35.4, 34.7, 34.5, 33.3, 31.9, 23.4, 20.5, 19.9, 16.3. Found: C 61.31%; H, 6.35%; C ₂₆ H ₃₁ F ₃ O ₇ . Calculated: C 60.93%; H, 6.10%.

Option 2

To a suspension of 0.5 g (0.807 mmol) of a mixture of 6α and 6β isomers of compound V in a mixture of 10 ml of toluene and 10 ml of methanol was added 0.32 ml (0.376 g) of 35% hydrochloric acid (0.13 g of hydrogen chloride, 3.556 mmol) hydrochloric acid and 1 ml of water. The reaction mass was stirred for 1 h at room temperature and transferred to a separatory funnel. The acidic layer was separated, extracted with toluene, and the extract was combined with the organic layer. The toluene solution was washed with 35% hydrochloric acid, water to a pH of 6-7, 5% aqueous ammonia and water until neutral. Then the solution was clarified with activated carbon and evaporated, removing the remaining toluene with methanol. The evaporation residue (0.323 g) contained a mixture of compounds III, VI and 17α, 21-dihydroxy-11β-trifluoroacetyloxy-6-methylene-pregn-4-en-3,20-dione in a ratio of 26: 57: 17% (HPLC). Column chromatography on SiO _{2 was} used to separate the mixture and identify compounds.

17α, 21-dihydroxy-11β-trifluoroacetyloxy-6-methylene-pregn-4-en-3,20-dione, mp 120-122 ° C. ¹ H NMR (400 MHz, CDCl _3, δ, ppm): 5.87 (1H, s, H-4), 5.67 (1H, q, 11-H, J = 2.8 Hz), 5.10 (1H, t 6-C = CH ₂ , J = 1.9), 5.01 (1H, t, 6-C = CH ₂ , J = 1.9), 4.27 dd, 4.64 dd (AB, 2H, 21-CH ₂ , J = 4.5, J = 19.9), 1.17 (3H, s, H-19), 0.80 (3H, s, H-18).

B. Scheme, option 2: III - IV - [V] - VI

Example 6. Obtaining 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylene-pregn-4-en-20-one (VI) Option 1

To the reaction mixture containing 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6ξ- (N-methyl-N-phenylaminomethyl) -pregna-4-en-3.20-dione (V), obtained from 0.5 g (0.972 mmol) 3-methoxy-21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxypregn-3,5-dien-20-one (IVa) according to variant 1 of the synthesis scheme (example 4), 0.38 ml (0.446 g) of 35% hydrochloric acid was added acid (0.156 g of hydrogen chloride, 4.283 mmol). The reaction mass was stirred at room temperature for 30 minutes, then diluted with 10 ml of methyl alcohol and poured into 20 ml of water. The precipitate was filtered off, washed on the filter with water to a pH of ~ 7 wash water, and dried to constant weight. Recrystallization from methanol gave 0.31 g (0.605 mmol) of compound VI with a yield of 62.24%, counting from IVa. Mp 187-190 ° C.

Option 2

To a solution of 0.215 ml (0.212 g, 1.98 mmol) of N-methylaniline in 1.25 ml of tetrahydrofuran was added 13 mg (0.068 mmol) of p-TSC monohydrate and 0.2 ml (0.218 g, 0.08 g in 100% calculation , 2.666 mmol) of a 37% formaldehyde solution. Then, with stirring and room temperature, a solution of 0.504 g (0.98 mmol) of 3-methoxy-21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxypregna-3,5-dien-20-one (IVa) in 2.5 ml of tetrahydrofuran was added . The reaction mass was stirred for 1 h at room temperature, then 20 ml of toluene and 0.38 ml (0.446 g) of 35% hydrochloric acid (0.156 g of hydrogen chloride, 4.283 mmol) were added. The reaction mass was stirred at room temperature for 30 minutes, and transferred to a separatory funnel. The acid layer was separated, the toluene solution was washed with 5% hydrochloric acid, water to a pH of 6-7, 1% aqueous ammonia and water until neutral. Then the solution was clarified with activated carbon and evaporated, removing the remaining toluene with methanol. 2 ml of methanol and 10 ml of water were added to the residue; the suspension was held for 30 minutes. at a temperature of 8-10 ° C, the precipitate was filtered off, washed on the filter with water, dried to constant weight. 0.326 g (0.636 mmol) of compound VI was obtained in 64.9% yield, counting from IVa.

Option 3

To 2 g (3,783 mmol) of 3-ethoxy-21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-pregn-3,5-dien-20-one (IVb) in 2 ml of triethylorthoformate was added 0.48 ml (0.474 g, 4.42 mmol) N-methylaniline. Then, a solution of 0.075 g (0.435 mmol) of p-TSC in 0.75 ml of ethanol and 0.41 ml (0.447 g, 0.165 g in 100%, 5.506 mmol) of a 37% formaldehyde solution was added dropwise. The reaction mass was stirred for 1.5 hours at room temperature and diluted with 20 ml of toluene. After this, 10 ml of acetone, 3 g (14.407 mmol) of barium chloride and 3 ml (4.336 g, 2.385 g in 100%, 24.31 mmol) of 55% sulfuric acid were added. The reaction mass was stirred at room temperature for 1 h, then worked up as described in Example 5. 1.83 g (3.571 mmol) of compound VI were obtained in 94.4% yield, counting from IVb.

B. Scheme, option 3: III - [IV] - V

Example 7. Obtaining 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6ξ- (N-methyl-N-phenylaminomethyl) pregn-4-en-20-one (V)

To a suspension of 5 g (9.99 mmol) of compound III in 7.5 ml of trialkyl orthoformate was added 0.125 g (0.725 mmol) of p-TSC. The reaction mass was stirred at room temperature for 15-30 minutes. After the completion of the reaction to obtain 3,5-dienol ether (IVa or IVb), 2.15 ml (2.122 g, 19.8 mmol) of N-methylaniline and 2 ml (2.18 g, 0.807 g in 100% calculation) were added to the reaction mass. 26.86 mmol) 37% aqueous formaldehyde solution. The reaction mass was stirred at room temperature for 2-2.5 hours. At the end of the reaction, to isolate a mixture of 6ξ- (N-methyl-N-phenylaminomethyl) epimers, the reaction mass was diluted with 20 ml of alcohol (methanol or 95% ethyl alcohol) and slowly poured into 200 ml of water. The precipitate was filtered off, washed on the filter with water to a pH of ~ 7 wash water, and dried to constant weight. Compound V (isomer mixture) was obtained in quantitative yield.

G. Scheme, option 4: III - [IV] - [V] - VI

Example 8. Obtaining 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylene-pregn-4-en-20-one (VI)

Option 1

To a suspension of 20 g (39.96 mmol) of 21-acetoxy-11-trifluoroacetyloxy-hydrocortisone (III) in 20 ml (17.82 g, 120.24 mmol) of triethylorthoformate was added 0.5 g (2.90 mmol) of p- TSC and stirred under argon flow at room temperature for 15 minutes. In this case, the dissolution of the precipitate of compound III and the formation of a gel-like mass of dark green were observed.

At the end of the reaction, the inert gas was stopped and 4.8 ml (4.74 g, 44.212 mmol) of N-methylaniline and 4.1 ml (4.489 g, 1.654 g in 100%, 55.063 mmol) of 37% aqueous were added slowly dropwise. formaldehyde solution. After adding N-methylaniline, a color change of the reaction mixture from dark green to reddish brown was observed. The reaction mass was stirred at room temperature for 1.5 hours

At the end of the aminomethylation reaction, 200 ml of toluene was slowly added to the reaction suspension with vigorous stirring. The reaction mass was stirred for 30 minutes at room temperature. The dissolution of the gel-like precipitate and the separation of the aqueous layer were observed. 50 ml of a 5% aqueous ammonia solution was added to the reaction solution, and the mass was stirred for 10 minutes. A change in color of the reaction mass from red to orange-yellow was observed.

The aqueous layer was separated and extracted with toluene three times. The organic layer and toluene extracts were combined and washed with 5% aqueous ammonia and water until neutral.

Thereafter, 150 ml of methyl ethyl ketone, 30 ml (43.36 g, 23.847 g in 100%, 243.15 mmol) of a 55% aqueous solution of sulfuric acid and 10 g () were added to a solution of compound V in toluene (~ 375 ml) with stirring. 90.11 mmol) calcium chloride. The reaction mass was kept at room temperature and vigorous stirring for 1 h. After the deamination reaction was completed, the reaction mass was transferred to a separatory funnel. The aqueous acidic layer, which is a thick red liquid, was separated from the organic layer and extracted with toluene three times.

The organic layer and toluene extracts were combined, washed sequentially with 5 ml of a 55% aqueous solution of sulfuric acid, with water to a pH of ~ 6-7 (in 10 ml portions); 5 ml of 5% aqueous ammonia and water until neutral.

After washing, the toluene solution of compound VI was dried with sodium sulfate and clarified with activated carbon. Then the solvent was evaporated (in vacuum or at atmospheric pressure). The toluene residue was removed by azeotropic distillation with ethanol.

After complete removal of toluene, 100 ml of ethanol was added to the residue in the cube at a temperature of 50-60 ° C and the mass was stirred at the same temperature until completely dissolved. A solution of compound VI in ethanol, cooled to a temperature of 40-45 ° C, was poured in a fine stream into 500 ml of water with vigorous stirring. The suspension was stirred for 30 minutes. at a temperature of 10-15 ° C, then kept without stirring for 2 hours at the same temperature. The precipitate was filtered and washed with water to pH ~ 7 wash water, dried to constant weight.

20.04 g (39.101 mmol) of 21-acetoxy-11-trifluoroacetyloxy-6-methylene-hydrocortisone (VI) were obtained in a yield of 97.85%. Mp 190-192 ° C.

Option 2

To a solution of 1.3 g (2.597 mmol) of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-pregn-4-ene-3,20-dione (III) in 2 ml (1,782 g, 12,024 mmol) of triethylorthoformate was added 16. 9 mg (98.13 mmol) p-TSC. The reaction mass was kept in a stream of dry nitrogen for 30 minutes. at room temperature, 0.56 ml (0.553 g, 5.16 mmol) of N-methylaniline and 0.52 ml (0.567 g, 0.21 g in 100%, 6.98 mmol) of an aqueous 37% formaldehyde solution were added. The reaction mass was held for 1.5 hours. Then 1 ml (1.174 g) of 35% hydrochloric acid (0.411 g of hydrogen chloride, 11.27 mmol) was added and stirred for 30 minutes. After that, 50 ml of ethyl acetate was added to the reaction mass, stirred vigorously for 1-2 minutes, transferred to a separatory funnel. The organic layer was separated and washed with water until neutral, the solvent was evaporated in vacuo. The residue was dissolved in 5 ml of methanol. The resulting solution was added dropwise with stirring to 50 ml of water, cooled to a temperature of 5-10 ° C. The suspension was stirred at the same temperature for 15 minutes, the precipitate was filtered off, washed with water to pH ~ 7 wash water, dried to constant weight. Obtained 1.28 g of the technical product of compound VI, which was crystallized from diethyl ether. Received 1.16 g (2.263 mmol) of compound VI with a yield of 87.15%, so pl. 189-191 ° C.

Option 3

To a suspension of 10 g (19.98 mmol) of 21-acetoxy-11-trifluoroacetyloxy hydrocortisone (III) in 15 ml (14.514 g, 136.77 mmol) of trimethylorthoformate was added 0.26 g (1.51 mmol) of p-TSC and stirred in a stream of argon at room temperature for 15 minutes In this case, dissolution of the precipitate of compound III was observed.

At the end of the reaction, the inert gas was stopped and 4.3 ml (4.244 g, 39.607 mmol) of N-methylaniline, 15 ml of toluene and 4.0 ml (4.36 g, 1.613 g in 100% calculation) were slowly added dropwise, 53, 72 mmol) 37% aqueous formaldehyde solution. The reaction mass was stirred at room temperature for 2 hours.

Then, 7.7 ml (9.04 g, 3.164 g of hydrogen chloride, 86.778 mmol) of 35% hydrochloric acid were added to the reaction solution, and the mass was stirred vigorously for 30 minutes.

At the end of the deamination reaction, the reaction mass was transferred to a separatory funnel. The aqueous layer was separated and extracted with toluene three times. The organic layer and toluene extracts were combined and washed with water to a pH of ~ 6-7 portions of 10-15 ml, 5 ml of 0.5% aqueous ammonia solution, and then with water until neutral.

After washing, the toluene solution of compound VI was dried with sodium sulfate and clarified with activated carbon. Then, the solvent was evaporated in vacuo, removing the toluene residue with methanol.

After complete removal of toluene, 20 ml of methanol and 100 ml of water were added to the residue in the flask with vigorous stirring. The suspension was stirred for 30 minutes. at a temperature of 10-15 ° C, then kept without stirring for 2 hours at the same temperature. The precipitate was filtered and washed with water to pH ~ 7 wash water, dried to constant weight.

8.28 g (16.156 mmol) of 21-acetoxy-11-trifluoroacetyloxy-6-methylene-hydrocortisone (VI) were obtained in a yield of 80.86%.

Option 4

To a suspension of 1 g (1.998 mmol) of 21-acetoxy-11-trifluoroacetyloxy-hydrocortisone (III) in 1 ml (0.891 g, 6.012 mmol) of triethyl orthoformate was added 5 ml of toluene and 0.026 g (0.151 mmol) of p-TSC and mixed under argon flow at room temperature for 15 minutes

At the end of the reaction, the inert gas was stopped and 0.43 ml (0.424 g, 3.961 mmol) of N-methylaniline and 0.4 ml (0.436 g, 0.161 g in 100%, 5.372 mmol) of a 37% aqueous solution were slowly added dropwise. formaldehyde. The reaction mass was stirred at room temperature for 2 hours.

Then, 0.77 ml (0.904 g, 0.316 g of hydrogen chloride, 8.678 mmol) of 35% hydrochloric acid was added to the reaction solution, and the mass was stirred vigorously for 30 minutes.

At the end of the deamination reaction, the reaction mass was diluted with 5 ml of toluene and transferred to a separatory funnel. The aqueous layer was separated and extracted with toluene three times. The organic layer and toluene extracts were combined and washed with water to a pH of ~ 6-7 three times in 5 ml portions, 1 ml of a 0.1% aqueous ammonia solution, and then in a 5 ml three times portions of water until neutral.

After washing, the toluene solution of compound VI was dried with sodium sulfate and clarified with activated carbon. Then, the solvent was evaporated in vacuo, removing the toluene residue with methanol.

After complete removal of toluene, 2.5 ml of methanol and 25 ml of water were added to the residue in the flask with vigorous stirring. The suspension was stirred for 30 minutes. at a temperature of 10-15 ° C, then kept without stirring for 2 hours at the same temperature. The precipitate was filtered and washed with water to pH ~ 7 wash water, dried to constant weight.

0.84 g (1.639 mmol) of 21-acetoxy-11-trifluoroacetyloxy-6-methylene-hydrocortisone (VI) was obtained in a yield of 82.03%.

Option 5

To a suspension of 3 g (5.994 mmol) of 21-acetoxy-11-trifluoroacetyloxy hydrocortisone (III) in 3 ml (2.903 g, 1.804 mmol) of trimethylorthoformate was added 3 ml of toluene and 0.075 g (0.436 mmol) of p-TSC and mixed under argon flow at room temperature for 15 minutes

At the end of the reaction, the inert gas was stopped and 1.29 ml (1.272 g, 11.883 mmol) of N-methylaniline, 1.2 ml (1.308 g, 0.483 g in 100%, 16.116 mmol) of a 37% aqueous formaldehyde solution were slowly added dropwise. and 15 ml of toluene. The reaction mass was intensively stirred at room temperature for 2 hours

Then, 2.31 ml (2.712 g, 0.948 g of hydrogen chloride, 26.034 mmol) of 35% hydrochloric acid 3 g of lithium chloride (70.034 mmol) was added to the reaction solution, and the mass was intensively stirred for 30 minutes.

At the end of the deamination reaction, the reaction mass was treated in the same way as in option 4.

2.78 g (5.424 mmol) of 21-acetoxy-11-trifluoroacetyloxy-6-methylene-hydrocortisone (VI) were obtained in a yield of 90.48%.

Example 9. Obtaining 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylpregna-4,6-diene-3,20-dione (VII)

Option 1

To a solution of 1 g (1.951 mmol) of 21-acetoxy-11-trifluoroacetyloxy-6-methylene-hydrocortisone (VI) in 25 ml of 96% ethanol was added 0.05 g of a catalyst (Pd / C or PdO / C) and 0.12 g of anhydrous acetate sodium. The mixture was heated to boiling and 0.1 ml of cyclohexene was added. The reaction mass was boiled with stirring for 0.5 h. The reaction progress was monitored by UV spectroscopy at a ratio of D ₂₈₆ / D ₂₅₈ , which should be at least 2.6-3.0. With this ratio of optical densities, the impurity of the starting compound VI should not exceed 1%.

At the end of isomerization, the hot suspension was filtered, the catalyst slurry was washed with 5 ml of hot ethanol in two stages. The reaction mass was slowly added dropwise to 300 ml of water, cooled to a temperature of 0-2 ° C. The precipitate was filtered off, washed with water until neutral, dried to constant weight.

0.942 g (1.834 mmol) of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methyl-pregna-4,6-diene-3,20-dione (VII) was obtained in 94.2% yield. T. pl. 219-221 ° C (sec.). ¹ H NMR (400 MHz, CDCl ₃ , δ, ppm): 6.01 (1H, br.s, H-7), 5.85 (1H, s, H-4), 5.65 (1H, m, H- 11), 5.07 (1H, d, J = 17.4 Hz, H-21), 4.70 (1H, d, J = 17.4 Hz, H-21), 2.16 (3H, s, CH ₃ C (O)), 1.87 (3H, s, 6-CH ₃ ), 1.20 (3H, s, H-19), 0.86 (3H, s, H-18). ¹³ C NMR (100.6 MHz, CDCl ₃ , δ, ppm): 204.9, 199.4, 170.6, 163.9, 137.3, 131.5, 120.6, 115.7, 88.8, 74.9, 67.7, 52.0, 49.0, 47.8, 35.9, 35.2, 34.6, 33.6, 33.5, 33.2, 23.0, 20.5, 19.9, 18.7, 16.1.

Option 2

Under the conditions of example 1 (option 2), from 500 mg (1.2 mmol) of 6-dehydro-6-methylhydrocortisone (IX) 21-acetate, 547 mg (1.067 mmol) of compound VII were obtained in 88.92% yield.

Example 10. Obtaining 17α, 21-dihydroxy-11β-trifluoroacetyloxy-6-methylpregn-4,6-diene-3,20-dione (11-trifluoroacetate 6-dehydro-6-methyl-hydrocortisone, VIII).

To a suspension of 2 g (3.902 mmol) of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylpregna-4,6-diene-3,20-dione (VII) in 40 ml of methanol was added dropwise with stirring at room temperature at room temperature a mixture of 10 ml of water and 2 ml of 35% hydrochloric acid. The reaction mass was kept at room temperature and stirring until the end of the reaction. A gradual dissolution of the crystals was observed. The reaction mass was diluted with 20 ml of water and extracted with dichloromethane three times. The combined extract (~ 100 ml) was washed twice with 10 ml of saturated sodium chloride solution and water to pH ~ 7. The solvent was evaporated to dryness in vacuo. The residue (1.84 g) was dissolved in dichloromethane and filtered through a 5-fold amount of SiO ₂ on a filter funnel, eluting with a dichloromethane-acetone mixture (9: 1 v / v). The filtrate was evaporated to dryness, the residue was triturated with ether, the precipitate was filtered off, washed with ether. Dried in vacuum at a temperature of 40-45 ° C to constant weight. 1.652 g of chromatographically pure compound VIII was obtained in 89.99% yield. Mp 135-137 ° C (from ether). ¹ H NMR (400 MHz, CDCl ₃ , δ, ppm): 6.03 (1H, br s, H-7), 5.83 (1H, s, H-4), 5.63 (1H, m, H- 11), 4.66 (1H, dd, J = 4.9, 19.9 Hz, H-21), 4.26 (1H, dd, J = 4.9, 19.9 Hz, H-21), 3.15 (1H, t, J = 4.9 Hz, 21-OH), 1.86 (3H, s, 6-CH ₃ ), 1.19 (3H, s, H-19), 0.84 (3H, s, H-18). ¹³ C NMR (100.6 MHz, CDCl ₃ , δ, ppm): 211.7, 199.4, 163.9, 137.1, 131.6, 120.6, 88.0, 74.8, 67.3, 52.0, 48.9, 48.2, 35.9, 35.3, 34.6, 33.6, 33.5.33.2, 23.1, 19.9, 18.7, 16.6.

Example 11. Obtaining 6-dehydro-6-methylhydrocortisone (I)

Option 1

To a suspension of 0.5 g (0.976 mmol) of 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxy-6-methylpregna-4,6-diene-3,20-dione (VII) in a mixture of 5 ml of methanol and 1 ml of water in a stream of nitrogen 2.5 ml (2.77 g, 0.278 g NaOH, 6.93 mmol) of a 10% aqueous sodium hydroxide solution were slowly added at room temperature for 30-40 minutes, periodically monitoring the pH of the reaction mixture (pH should be no more than 8). The reaction mass was kept at room temperature in a stream of nitrogen for 15 minutes. At the end of the reaction, the reaction mass was neutralized with a 5% hydrochloric acid solution and 20 ml of water was added. The reaction mass was stirred for 5 minutes, then extracted with dichloromethane. The organic layer was separated, the aqueous was extracted twice with dichloromethane. The combined extracts (~ 50 ml) were washed twice with 5 ml of water until neutral. Then the solution was treated with activated carbon. The solvent was evaporated in vacuo to stop the run. To the residue was added 2 ml of diethyl ether. The suspension was boiled for 30 minutes, cooled to room temperature. The precipitate was filtered off, washed on a filter with 0.5 ml of ether, dried to constant weight. Received 0.188 g (0.502 mmol) of compound I (1 crystallize) with a yield of 51.51%, so pl. 194-195 ° C. The mother liquor was evaporated to dryness, the residue (198 mg) was dissolved in dichloromethane and filtered through a 5-fold amount of SiO ₂ on a filter funnel, eluting with a dichloromethane-acetone mixture (4: 1 by volume). The filtrate was evaporated to dryness, the residue was triturated with ether, the precipitate was filtered off, washed with ether. Received 131 mg (0.35 mmol) of chromatographically pure compound I (2 crystallisate) with a yield of 35.89%, so pl. 192-194 ° C. The total yield of 11β, 17α, 21-trihydroxy-6-methyl-pregna-4,6-diene-3,20-dione (I) is 87.4%. ¹ H NMR (400 MHz, CDCl ₃ , δ, ppm): 6.05 (1H, br s, H-7), 5.76 (1H, s, H-4), 4.72 (1H, s, 17- OH), 4.67 (1H, dd, J = 4.8, 19.6 Hz, H-21), 4.38 (1H, m, H-11), 4.25 (1H, dd, J = 5.3, 19.6 Hz, H-21), 3.54 (1H, t, J = 4.9 Hz, 21-OH), 3.35 (1H, d, J = 2.5 Hz, 11-OH), 1.83 (3H, s, 6-CH ₃ ), 1.33 (3H, s, H-19), 0.94 (3H, s, H-18)

Option 2

Under the conditions of option 1, from 500 mg (1.063 mmol) of 11-trifluoroacetyloxy-6-dehydro-6-methylhydrocortisone (VIII), 347 mg (0.926 mmol) of compound I was obtained in 87.1% yield, so pl. 192-194 ° C.

Example 12. Obtaining 21-acetoxy-11β, 17α-dihydroxy-6-methylpregn-4,6-diene-3,20-dione (IX)

Option 1

To a suspension of 0.5 g (1.355 mmol) of 6-dehydro-6-methylhydrocortisone (I) in 5 ml of acetone was added 0.5 ml (0.363 g, 3.587 mmol) of triethylamine and 0.1 ml (0.108 g, 1.056 mmol) of acetic anhydride. The reaction mass was stirred at room temperature. At the end of the reaction, the reaction mass was poured slowly into 50 ml of water, cooled to 10-15 ° C, the suspension was kept for 2 hours with stirring and 1 hour without stirring. The precipitate was filtered off, washed on the filter with distilled water to a pH of ~ 7, and dried to constant weight in vacuo. 0.52 g (1.248 mmol) of compound IX was obtained with a yield of 93.48%. Mp 144-145 ° C. ¹ H NMR (400 MHz, CDCl ₃ , δ, ppm): 6.04 (1H, br.s, H-7), 5.79 (1H, s, H-4), 5.02 (1H, d, J = 17.4 Hz, Н-21), 4.89 (1H, d, J = 17.4 Hz, Н-21), 4.45 (1Н, m, Н-11), 2.17 (3Н, s, СН ₃ С (O)), 1.84 (3H, s, 6-CH _3), 1.32 (3H, s, H-19), 0.97 (3H, s, H-18). ¹³ C NMR (100.6 MHz, CDCl ₃ , δ, ppm): 205.1, 200.6, 171.0, 166.0, 139.0, 130.9, 123.3, 119.8, 89.4, 68.2, 67.5, 53.3, 49.5, 48.4, 39.3, 36.4, 33.5, 33.3, 33.1, 23.1, 20.6, 19.8, 18.9, 16.7.

Option 2

Under the conditions of the patent [US 4330541, 1982, Example 1], from 500 mg (0.976 mmol) of 21-acetoxy-17α-hydroxy-11-trifluoroacetyloxy-6-methylpregn-4,6-diene-3,20-dione (VII), 353 mg (0.848 mmol) of compound IX in 86.89% yield. Mp 146-148 ° C.

Claims (69)

1. The method of obtaining 6-dehydro-6-methylhydrocortisone (11β, 17α, 21-trihydroxy-6-methylpregna-4,6-diene-3,20-dione) or its esters of General formula I

where R = COCF ₃ or H; R ₁ = COSH ₃ or H, from 21-hydrocortisone acetate of formula II

a sequence of transformations involving the protection of the 11β-hydroxyl group by esterification with a trifluoroacetic acid derivative in an aprotic solvent under basic catalysis using an effective amount of a catalyst to form 21-acetoxy-17α-hydroxy-11β-trifluoroacetyloxypregn-4-en-3,20-dione of the formula III

Eno-esterification of the Δ ⁴ -3-ketosystem of the obtained compound by the action of trialkyl orthoformate in the presence of an acid catalyst with the formation of the 3-alkoxy ester Δ ^3,5 -3-hydroxy derivative of the general formula IV

where R = CH ₃ or CH ₂ CH _3, condensing it with a Mannich reagent formed in situ from formaldehyde and a secondary amine in the presence of an acidic catalyst to form a mixture of 6- and 6β-isomers of 6- (N-methyl-N-phenyl) -aminomethyl derivative of the general formula V

the splitting of the resulting mixture of Mannich steroid bases on the C-N bond by the action of protic mineral acid in the presence of salts of hydrohalic acid with the formation of a 6-methylene derivative of formula VI

isomerization of the 6-exomethylene bond to the 6,7-endomethylene; the removal of the protective groups of 11β- and 21-hydroxyl groups in whole or in part; esterification of the 21-hydroxyl group with an acetic acid derivative under basic catalysis. 2. The method according to p. 1, characterized in that for the esterification of the 11β-hydroxyl group of compound II, trifluoroacetic acid anhydride is used as the trifluoroacetic acid derivative. 3. The method according to p. 1, characterized in that the esterification of the 11β-hydroxyl group of compound II is carried out in an aprotic solvent, which is used dialkyl ketones, or cyclic ethers, or dimethyl sulfoxide under basic catalysis using a catalyst in the amount necessary for complete conversions of the starting compound. 4. The method according to p. 3, characterized in that the dialkyl ketone is selected from the group comprising acetone, methyl ethyl ketone. 5. The method according to p. 3, characterized in that the cyclic ethers are selected from the group comprising tetrahydrofuran, dioxane. 6. The method according to p. 1, characterized in that as a catalyst for the esterification of the 11β-hydroxyl group of compound II using heteroaryl compounds, or alkyl amines, or mixtures thereof. 7. The method according to p. 6, characterized in that pyridine or its derivatives are used as heteroaryl compounds. 8. The method according to p. 7, characterized in that dimethylaminopyridine is used as the pyridine derivative. 9. The method according to p. 7, characterized in that triethylamine is used as the alkylamine. 10. The method according to p. 1, characterized in that protic acids are used as the acidic catalyst for the enolization of the Δ ⁴ -3-ketosystem of compound III for esterification to form the 3-alkoxy ester Δ ^3,5 -3-hydroxy derivative of the general formula IV. 11. The method according to p. 10, characterized in that the use of mineral or organic acids as protic acids. 12. The method according to p. 11, characterized in that the mineral acids are selected from the group of water-soluble oxygen-containing or oxygen-free acids. 13. The method according to p. 12, characterized in that the water-soluble oxygen-containing acids are selected from the group comprising perchloric, sulfuric, nitric acids. 14. The method according to p. 12, characterized in that the water-soluble oxygen-free acids are selected from the group comprising hydrochloric acid. 15. The method according to p. 11, characterized in that sulfonic acids are used as organic acids. 16. The method according to p. 15, characterized in that the sulfonic acid is selected from the group comprising sulfosalicylic acid, p-toluenesulfonic acid. 17. The method according to p. 1, characterized in that the formation of the 3-alkoxy ester Δ ^3,5 -3-hydroxy derivative of General formula IV is carried out in a trialkylorthoformate medium. 18. The method according to p. 17, characterized in that as a trialkyl orthoformate use trimethyl orthoformate or triethyl orthoformate. 19. The method according to p. 1, characterized in that the formation of the 3-alkoxy ester Δ ^3,5 -3-hydroxy derivative of General formula IV is carried out in a proton or aprotic solvent or a mixture thereof. 20. The method according to p. 19, characterized in that aliphatic alcohols are used as protic solvents. 21. The method according to p. 20, characterized in that the aliphatic alcohols are selected from the group comprising methanol, ethanol. 22. The method according to p. 19, characterized in that cyclic ethers or aromatic hydrocarbons of a number of benzene are used as aprotic solvents. 23. The method according to p. 22, characterized in that the cyclic ethers are selected from the group comprising dioxane, tetrahydrofuran. 24. The method according to p. 22, characterized in that the aromatic hydrocarbons of a number of benzene are selected from the group comprising benzene, toluene. 25. The method according to p. 1, characterized in that the condensation of the compounds of General formula IV with a reagent obtained from formaldehyde and a secondary amine is carried out in a proton or aprotic solvent. 26. The method according to p. 25, characterized in that aliphatic alcohols are used as the proton solvent. 27. The method according to p. 25, characterized in that as an aprotic solvent, cyclic ethers or aromatic hydrocarbons of a number of benzene. 28. The method according to p. 26, characterized in that the aliphatic alcohols are selected from the group comprising methanol, ethanol. 29. The method according to p. 27, characterized in that the cyclic ethers are selected from the group comprising dioxane, tetrahydrofuran. 30. The method according to p. 27, characterized in that the aromatic hydrocarbons of a number of benzene are selected from the group comprising benzene, toluene. 31. The method according to p. 1, characterized in that the condensation of the compounds of general formula IV with a reagent obtained from formaldehyde and a secondary amine is carried out in a trialkyl orthoformate medium or in a mixture of trialkyl orthoformate and an organic solvent without isolating the compound of general formula IV from the reaction mass. 32. The method according to p. 1, characterized in that the cleavage of the mixture of steroid Mannich bases of the general formula V via the C-N bond is carried out in an aprotic solvent or a mixture of aprotic solvents by the action of mineral acids. 33. The method according to p. 32, characterized in that the use of hydrochloric acid or sulfuric acid as mineral acids. 34. The method according to p. 32, characterized in that as mineral acids use 30-35% aqueous solution of hydrochloric acid or 50-70% aqueous solution of sulfuric acid. 35. The method according to p. 1, characterized in that as the salts of halogen acid use salts of alkali or alkaline earth metals, or ammonium, and hydrochloric or hydrobromic acids. 36. The method according to p. 1, characterized in that the isomerization of the 6-exomethylene bond of the compounds of formula VI with the formation of the 6,7-endomethylene bond is carried out in the presence of a palladium catalyst. 37. The method according to p. 36, characterized in that palladium or palladium oxide adsorbed on carbon is used as a palladium catalyst. 38. The method according to p. 1, characterized in that the removal of the protective group of the 21-hydroxyl group is carried out by the method of acid solvolysis, both with or without isolation of the product of isomerization of the 6-exomethylene bond into the 6,7-endomethylene from the reaction mass to form a common compound formula I, where R = COCF ₃ and R ₁ = N. 39. The method according to p. 1, characterized in that the cleavage of the mixture of steroidal Mannich bases of the general formula V via the C-N bond is carried out without isolating them from the reaction mass. 40. The method according to p. 1, characterized in that for the esterification of the 21-hydroxyl group of compound I, acetic anhydride is used as the acetic acid derivative. 41. The method according to p. 1, characterized in that the esterification of the 21-hydroxyl group of compound I is carried out in an aprotic solvent, which is used dialkyl ketones or cyclic ethers under basic catalysis using an effective amount of catalyst. 42. The method according to p. 41, characterized in that the amount of catalyst used is the minimum necessary for the complete conversion of the starting compound. 43. The method according to p. 41, characterized in that the dialkyl ketone is selected from the group comprising acetone, methyl ethyl ketone. 44. The method according to p. 41, characterized in that the cyclic ethers are selected from the group comprising tetrahydrofuran, dioxane. 45. The method according to claim 1, characterized in that ammonia derivatives are used as a catalyst for the esterification of the 21-hydroxyl group of compound I at R = R ₁ = H. 46. The method according to p. 45, characterized in that heteroaryl compounds or alkyl amines or mixtures thereof are used as ammonia derivatives. 47. The method according to p. 46, characterized in that the heteroaryl compounds are selected from the group consisting of pyridine and its derivatives. 48. The method according to p. 47, characterized in that as derivatives of pyridine use compounds selected from the group comprising dimethyl aminopyridine. 49. The method according to p. 46, characterized in that the alkylamines are selected from the group comprising triethylamine. 50. The method according to p. 1, characterized in that for the esterification of the 11β-hydroxyl group of compound I at R = H and R ₁ = COCH ₃ , trifluoroacetic acid anhydride is used as the trifluoroacetic acid derivative. 51. The method according to p. 1, characterized in that the esterification of the 11β-hydroxyl group of compound I at R = H and R ₁ = COCH _{3 is} carried out in an aprotic solvent, which is used dialkyl ketones, or cyclic ethers, or dimethyl sulfoxide under basic conditions catalysis using an effective amount of catalyst. 52. The method according to p. 51, characterized in that use the amount of catalyst necessary for the complete conversion of the starting compound. 53. The method according to p. 51, characterized in that the dialkyl ketones are selected from the group comprising acetone, methyl ethyl ketone. 54. The method according to p. 51, characterized in that the cyclic ethers are selected from the group comprising tetrahydrofuran, dioxane. 55. The method according to p. 1, characterized in that dimethylaminopyridine is used as a catalyst for the esterification of the 11β-hydroxyl group of compound I at R = H and R ₁ = COCH ₃ .