UA81133C2 - Process of stereospecific synthesis of 3-hydroxy-5?-h steroidal sapogenins, process of conversion and processes for the preparation of smilagenin and epismilagenin - Google Patents

Abstract

A method to stereospecifically prepare a steroidal sapogenin or a derivative thereof by reducing a steroidal sapogenin with a hindered organoborane oran organo-aluminium hydride. A steroidal sapogenin or derivative thereof may be prepared by reducing the steroidal sapogenin using as reducing agent a relatively highly hindered organoborane reagent or by SN 2 inversion of a steroidal sapogenin or derivative thereof. The organo-aluminium hydride may be used to prepare a steroidal sapogenin or derivative thereof. The invention provides a convenient route to useful steroidal sapogenins such as sarsasapogenin, episarsasapogenin, smilagenin, epismilagenin and esters thereof, from readily available or easily preparable starting materials (e.g. diosgenone, preparable from diosgenin).

Description

Description of the invention

This invention relates to the stereospecific synthesis of 3-hydroxy-5p-H steroidal sapogenins and their derivatives. 2 The specified sapogenins and their derivatives (more specifically, sapogenins having a 5p-H atom, and more specifically, compounds having a 3-OH group and a 5pD-H atom, such as sarsasapogenin, episarsasapogenin, smilagenin and epismilagenin) are known to be used in the treatment of cognitive dysfunction and other conditions. Such their activity is described, for example, in patents MUO-99/48482, М/О-99/48507, М/О-01/49703, МО-02/079221 and МУО-01/234061, 70 descriptions of which are included here by reference This publication uses the same naming system for rings and carbon atom positions as in previous publications.

Methods of synthesis of 3-hydroxysteroid sapogenins are described in the literature. For example, synthesis

3-hydroxy-50-H steroids from the corresponding 3-keto-50-H steroids, which is carried out with sodium borohydrate in tetrahydrofuran (THF) and methanol or using lithium aluminum hydride in diethyl ether (Neim. Spit. 7/5. Asia, 66, 192-217 (1983). (US Patent No. 3875195 (1975)), incorporated herein by reference, describes the catalytic reduction of 3-keto-5D-H steroids to 3-hydroxy-5p-H steroids in a lower carboxylic acid with a nickel Raney catalyst and hydrogen under pressure. The researchers note that the reduction by

Meyerwein-Pondorf-Werle (MPV) gives a mixture of Ze- and Zr-hydroxy steroids in equal parts. It is noted that it is difficult to separate such mixtures.

After the introduction of a family of highly hindered trialkylborohydride reducing agents, commonly known as

ZeiIesihidez?, which began in the early 70s |Vhom/up ei aiY., ). At. Spent boss. 94, 7159-7161 (1972), a number of publications appeared that described the use of these reducing agents in specific methods of sterol synthesis. For example, in (Z(egoidz, 36,299-303 (1980), e(egoidz5, 45,39-51 (1985), U. Spet. Bos. Sottip. Ha 1239-1240 (1982), Teigapeagop, 40,851-854 ( 1984), NeMm. Spit. Asia, 66,192-217 (1983), in US Patent No. Mob150336 (2000) and Teiganedgop, 45,3717-3730 (1989), which are incorporated herein by reference, describe i9) stereospecific transformations by with the help of Zeiesigide (certain Z-keto-br and Z-keto-bsa steroids in the appropriate

ZV-OH, 5D-H and Zo-OH, 50-H sterols.

In relation to steroidal sapogenins, the synthesis of smilagenin was described by the reduction of smilagenon with aluminum co-isopropylate in isopropyl alcohol, the reduction of MPV (|MagkKeg ei aiYi, U. Ateg. Spet. 5os., 622525 p. (1940). Marker reported that the reduction of MIV of sarsasapogenins gives a mixture of sarsasapogenin and episarsasapogenin (Magkeg apa Kopgtapp, y). Ateg. Spet. Zos, 61,943 (1939)). Descriptions of these publications are included in. this application is a link. -

Researchers have also discovered specific catalytic hydrogenations, such as Blunden's synthesis of epitigogenin from tigogenone using hydrogenation over an Adams catalyst (platinum oxide (IM)) (ee) in glacial acetic acid, which contains 295 hydrochloric acid |). May Year 42, 478-482 (1979);

Opdegvieroogi U. Mei. Kev., 61,351-359 (1994) Marker found that hydrogenation of sarsasapogenone over an Adams catalyst in ethanol gave episarsasapogenin |MagKeg apa Kopgtapp, .). Ateg. Spent wasps, 61,943 (1939)|. "

Reductions using sodium borohydride are also reported, for example, the synthesis of episarsasapogenin from sarsasapogenone by Miles using sodium borohydride |U. Aadgis. - with Eosd Spet., 41,914-917 (1993)). Reduction with lithium aluminum hydride is also reported, and for example, the synthesis of epismilagenin from smilagenon by Djerassi (U. At. Spect. Bos, 74, 422-424, (1952)) and the synthesis of episarsasapogenin from sarsasapogenon by Lewis (|Ziegoidz, 58,387-389 (1993)). The descriptions of these publications are incorporated herein by reference. ee) in the form of a reference, give methods for the synthesis of C y-hydroxy-5y-H sapogenins using K-ZeiesigideF at - low temperatures.

In Ipatent MMO-02/079221, published 10.10.2002), in example 6, the synthesis of episarsasapogenin is described by the reduction of sarsasapogenone using lithium tri-tert-butoxyaluminum hydride. However, this publication is not considered prior art in all of these 50 countries.

In this invention, an attempt was made to improve the stereospecific synthesis of 3-hydroxy-5p-hydrogen c" steroidal sapogenins, and, more preferably, 3p-hydroxy-5D-H-sapogenins, which are defined and described in (publications Ukhmo-99/48482, M /О-99/48507, МО-01/49703, УМО-02/079221 and МУО-01/234061, as well as their derivatives, such as, for example, the corresponding saponins and other physiologically acceptable forms, such as salts and ethers that can serve as prodrugs.

F! In the most preferred embodiment of the present invention, an attempt has been made to provide effective stereospecific synthesis of sarsasapogenin, smilagenin, episarsasapogenin, epismilagenin, their prodrugs and other physiologically acceptable forms.

The present invention presents, first of all, a method of obtaining C-hydroxy-5 D-H steroid sapogenin or its 60 derivative, which includes the reduction of C-keto-5 D-H steroid sapogenin using a reducing agent, such as a hindered organoborane or organoaluminum hydride.

C-Hydroxy-5D-H steroidal sapogenin, which is previously formed by said stereospecific reducing agents, can then be converted into the desired derivative, for example, using derivatization techniques well known in the art. This transformation can occur in the same or in another reaction system, and can occur simultaneously with the reduction or after it.

The term "hindered organoborane" herein refers in particular to alkali metal -trialkyl- or triaryl-borohydride reducing agents such as, for example, lithium tri-zes-butylborohydride, lithium trisiamylborohydride or lithium triphenylborohydride, or to corresponding reducing agents in which lithium is replaced by sodium or potassium

Alkyl groups preferably contain from 1 to 7 carbon atoms, most preferably from 3 to 7 carbon atoms.

Aryl groups preferably contain from 6 to 12 carbon atoms and may be alkyl substituted. The reductants referred to in this specification have the generic name "Zeiesigide", although it is to be understood that the term "Zeiesigide" as used herein does not limit the invention to a reductant that is obtained from a specified manufacturer or from a specified source, and such a reductant may be used . For a more detailed 70 discussion, we refer to |"Kedisiope ru (She AIshtipo-apa Vogopuagidez ip Ogdapis Zupipeziv", ). Zeudep-Reppe (MSN Rybiizpegv, Ips.)). Predominantly hindered organoboranes for use according to the present invention are lithium tri-zes-butylborohydride (I-Zeieshydride), potassium tri-zes-butylborohydride (K-Zeiesyhide), sodium tri-zes-butylborohydride (M-Zeiesyhydride), lithium trisiamylborohydride (I 5 -ZeiIesigide), potassium trisiamylborohydride (K5-Zeiesigide), sodium triphenylborohydride and lithium triphenylborohydride.

The term "organoaluminum hydride" as used herein refers in particular to any reducing agent containing aluminum, a hydride component, and organic groups (e.g., alkyl or alkoxy containing from 1 to 7 carbon atoms, respectively), such as sodium bis-( 2-methoxyethoxy)aluminum hydride (Kea-A!F), diisobutyl-aluminum hydride or lithium tri-tert-butoxyaluminum hydride (LIBA). For a more detailed discussion, we refer to

GKedisipz Bu (pe APIshtipo-api Vogopuagidez ip Ogdapis Zupipeviv", U. Zeudep-Reppe (MSN Rybiizpegv, Ips.)). The preferred organoaluminum hydrides for use according to the present invention are sodium bis(2-methoxyethoxy)aluminum hydride (Kea-AI) , diisobutylaluminum and LTBA.

The expression "derivative" used herein in relation to sapogenins refers, in particular, to the corresponding saponins and other physiologically acceptable forms, such as salts and esters, which can serve as prodrugs.

Sapogenins and other derivatives can readily interconvert by reactions well known in the art. сч ов Sapogenin derivatives can carry derivative groups in any given, one or more, position in the molecule.

Saponin and its ether derivatives may carry, for example, derivative groups in the C-position of ring A. The expression i) "sapogenin" as used herein will include all derivative forms thereof, unless the contrary is obvious from the context.

In connection with the third aspect of the present invention, which is discussed below, the term "derivative" as used herein also refers to activated sapogenin derivatives used in the reaction.

By appropriate selection of the reducing agent, the method allows obtaining a number of substances -3 o-hydroxy, 5рД-Н and Зр-hydroxy, and 5Д-Н and their derivatives - mainly or at least mainly as reaction products in the stereoisomerically pure form of пе (for example, about 8095 rearrangement) from available commercial or previously prepared starting reactants, usually to avoid difficult separation of mixtures of isomers. --

The use of hindered organoborane or organoaluminum hydride as a reducing agent has not previously been applied to 3-keto-5p-H steroidal sapogenins. The synthesis of episarsasapogenin, the description of which is incorporated herein by reference, was performed by Miles |U. Adgis Rosd Spet., 41,914-917 (1993)) using sodium borohydride as a reducing agent, while the more selective LIBA reagent was already "known at the time when this work was reported.

If the reductant is a relatively highly complicated organoborane (organic groups with more than two carbon atoms), the resulting sapogenin can be, preferably, Zr-hydroxy-5 D-H sapogenin. If the reducing agent is a relatively less complicated organoborane (organic groups with no more than two carbon atoms), the resulting sapogenin can be, preferably, 2-hydroxy-5D-H sapogenin.

If the reducing agent is an organoaluminum hydride, then the sapogenin obtained can be, preferably,

Zo-hydroxy-5D-H sapogenin. The expression "Z-keto-5p-H sapogenin"; used here for convenience, means the starting material for - reduction and does not necessarily imply the presence or absence of keto groups in other parts of the molecule, for example, outside the A ring, when provided that, if necessary, any undesired reactive sites in other parts of the molecule are protected accordingly.The starting material 3-keto-5|3-H sapogenin may have differences in CO 20 compared to the desired reaction product in parts of the molecule except position of C in ring A, in which case the necessary transformation will be performed in a manner known to one skilled in the art as part of the total synthesis, c'' which gives the desired final product.

The starting substance З-keto-5р-Н sapogenin can be easily obtained by oxidation of the corresponding З3-ОН sapogenin.

For example, sarsasapogenone can be prepared by oxidation with pyridine dichromate as described by Miles.

Adgis Rosa Spet., 41,914-917 (19933), by Jones oxidation as described by Blunden |U. May Rhod., 42,478-482

GF) (1979)) and in (patent UUO-98/07741, the descriptions of which are included in this application in the form of references. Smilagenon is obtained from diosgenone (which is directly formed by the oxidation of diosgenin) using the reduction of the double bond o,p of an unsaturated ketone |Magkeg ei ai!., u. At. Spet. os. 2525 (1940), Igiztefom 5 Soguaem, I2u. AkKaai.

Maik Ka. Z5K, Zeg. Kpit., 2,47-52 (1981)). because in the preferred embodiment of the present invention, the starting substance is 3-keto-5D-H steroidal sapogenin, obtained by heterogeneous catalytic hydrogenation of the corresponding 1?-3-keto steroidal sapogenin, for example, diosgenon. Heterogeneous catalytic hydrogenation converts the L"-3-keto steroid sapogenin into the corresponding 5D-H ketone, for example, smilagenone, which is then reduced in accordance with the first aspect of the present invention.

Heterogeneous catalytic hydrogenation can accordingly be performed using hydrogen and a palladium catalyst in an organic solvent. The palladium catalyst is supported on a support such as, for example, barium sulfate, calcium carbonate, graphite, or carbon. The palladium catalyst is preferably used in a pre-reduced form.

If diosgenone is the reactant and the catalytic hydrogenation is accompanied by the reduction of smilagenon using a hindered organoborane as a reducing agent, the product of the reaction is smilagenin.

If diosgenone is a reactant and catalytic hydrogenation is accompanied by the reduction of smilagenon using organoaluminum hydride as a reducing agent, the reaction product is epismilagenin.

In its second aspect, the present invention presents a method of converting C o-hydroxy-5p-H steroid 70 sapogenins and their derivatives into Cp-hydroxy-5D-H steroid sapogenins and their derivatives, which includes the reaction of the activated C-hydroxy derivative of Zo-hydroxy-5p -H of a steroidal sapogenin with a nucleophilic reagent under conditions favorable for nucleophilic substitution with inversion at position C with optional subsequent placement of a substituting group at position 3, if necessary.

The reaction will proceed according to the Z2 mechanism, which will lead to the necessary inverted product of the reaction. Synthesis scheme 75, which can be detailed, is the Mitsunobu reaction (Nidnez, Ogdapis Keasiopv, 42,337-400 (1992)). If this synthesis scheme is applied to sapogenin, then 3-OH sapogenin is converted through its 3-hydroxy activated form into the corresponding 3-ester with inversion in position 3. The reagents used are dialkyl azodicarboxylate, triarylphosphine and the corresponding organic acid or its salt according to necessary ether. The term "alkyl" preferably refers to alkyl groups containing from 1 to 7 carbon atoms. The term "aryl" preferably refers to aryl groups containing from 6 to 12 carbon atoms, and such aryl groups may be optionally alkyl-substituted.

An alternative synthesis scheme may include the initial synthesis of an activated sapogenin derivative capable of nucleophilic substitution, for example, an organic derivative that is sulfonated in the 3-0 position, such as a 3-mesylate or 3-tosylate derivative. Ge

If the organic acid used in said reaction according to the second aspect of the present invention includes a group, such as an amino group, which may participate in an undesirable reaction, this group will be appropriately protected in a conventional manner.

In general, the present invention provides a method for the synthesis of desirable steroidal sapogenins, e.g., smilagenin or epismilagenin, from readily available starting materials, e.g., diosgenin, using co-selective reduction under stereochemical control, as shown for these specific compounds in Scheme 1, which is presented below : «- «- d) - . and? (ee) - - (95) syu» ime) 60 b5

Scheme 1 and NuRa- VakhO/uTGgF o o n

DIOSGENONE SMILAGENONE

LIBALTF I-BeIsestas/GF se o o (o)

But" N and Ge)

EPISMILATGENIN SMILAGENIN c «- «-

RESOSY Prydyn (Sispsia, 1965, 24, 89) so

RISON/RV;R

ROZHSMAMSORg ' ! 5 « - with from

RYSOY n ee) SMILAGENIN BENZOATE - - The methods of this invention can be used to prepare 3-hydroxy 5 D-H steroidal sapogenin, 5or such as sarsasapogenin, smilagenin, episarsasapogenin, epismilagenin and their derivatives. Prodrugs and other physiologically acceptable forms of sapogenins can be obtained from 3-OH compounds by a generally accepted method, which is described in more detail below.

Sapogenin synthesis products

In the method of obtaining sapogenin synthesis products according to this invention, substances of the general formula are preferably used: (Ф) kobo b5

Ka o

In ; IN; 70 5 7

Ko o.

EC,

Kg

Kb N

Kz K. c o e Ku, Bo, Kz, Ku, KB, Kv, Ku, Kv and Ku, independently of each other, are H, C..4 alkyl, OH or OK (where K -

St." aryl or C. in alkyl), or Kb and Ke5 together can represent -O (carbonyl) or a protected carbonyl group, the stereochemistry of the carbon atom in position C (namely, the carbon of ring A to which the group K40 is attached) can be c 20 or K or 5, and Clio can be OH, an O-linked hydrocarbon group, or any organic ether group (which includes aliphatic and amino acid esters). (ze)

In addition to the case described in the above formula, using the dot-dashed model of the molecule, "- in addition, since stereospecificity is a feature of this invention, the stereochemistry of the formula is not given, and all stereoisomers and mixtures of isomers are included. - with The expression "physiologically acceptable prodrugs" here means those prodrugs of the compounds used in accordance with the present invention, which, within the framework of a reliable clinical evaluation, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, etc. similar, according to an acceptable benefit/risk ratio, as well as zwitterionic forms, if possible, of the compounds of the invention. The term "prodrugs" means compounds that are rapidly transformed into a product of the reaction of the parent substance of the formula mentioned above, for example, by hydrolysis in the blood. A detailed discussion of prodrugs is presented in the following sources: (Oevidp oi Rgodgidv, N. Vypadaaga, Ed., Eivemieg, 1985; Meiyodz ip Eplutoiodu, K. UMUiddeg ei ai, p. E49., Asadetis Rgezv, 42, p. 309-396, 1985; A Tehirook oi Ogid Oezidp apa OemeIortepi, Kgodzdaaga-I aggep apa nN. :z" Vypdadaaga, Ed. , Sparieg 5; Oevidp apa Arriisayope oi Rgodgidv, p. 113-193, 1991; Admapsey Ogoid Oeimigu

Kemiemuv, N. Vypadaaga, 8, pp. 1-38 (1992); doigpa! oh Rpagtaseciisa! Zsiepsev, 77, p. 285 (1988); Spent RNAKM. 15 YOU ., M. MaKeua eyi aiYi, 32, p. 692 (1984); Rgo-dgydz az Mome! Oeiiimegu Bzuvietv, T. Nidispi apa M. egeia, so MoI.14 oi She A. S. 5. Zutrovisht Zegiev, ap Viohemegvirie Sagiegz ip YuOgid YuOezidp, Eduaga V. Kospe, Ea.,

Ategisap Ripagtaseciisa| Azzosiayop apa Regdatop Rgezvz, 1978, which are included in this application as a reference. The expression "physiologically acceptable salts" means relatively non-toxic, inorganic and organic - acid-addition salts of the compounds of the present invention. These salts can be obtained directly during the final isolation and purification of the compounds or by reaction of individual purified compounds. See, for example , article 5. M. (95) Vegode eyi a), Rpaptaseshiisa! Zai(v, 9. Rpagt. Zsi., 66: p.1-19 (1977), which is incorporated here by reference). "c" Expression " "organic ether" herein means any ester obtained by the reaction of a compound where Co is OH with an ether-forming organic acid or its activated derivatives. The organic acid may be, for example, an aliphatic carboxylic acid or an amino acid. Without limitation, the group organic ether vv Can, for example, be selected from: catylate (ethoxycarbonyloxy), acetate, succinate, propionate, p-butyrate, ibutyrate, valerate, isovaleriate, p-caproate, isocaproate, diethyl acetate, octanoate, decanoate, laurate, (F) myristate , palmitate, stearate, benzoate, phenylacetate y, phenylpropionate, cinnamate, phthalyl, glycinate,

He alaninate, valinate, phenylalanine, isoleucinate, methioninate, argininate, aspartate, cysteinate, glutaminaiu, histidinate, lysinate, prolinate, serinate, threoninate, tryptophanate, tyrosinate, fumerate, to Maleate, substituted aliphatic, for example, chloroacetate, methoxyacetate, protected groups of amino acids esters, for example, Bos-aminoglycinate (Bos,-butoxycarbonyl), Bos-aminovalinate, CB72-aminoglycinate (CB7-benzyloxycarbonyl), CB/7-aminoalinate, and groups of substituted aromatic ethers, for example, p-bromobenzoyloxy, t-bromobenzoyloxy, p-methoxybenzoyloxy, a chlorobenzoate such as p-chlorobenzoyloxy, a dichlorobenzoate such as 2,4-dichlorobenzoyloxy, a nitrobenzoate such as p-nitrobenzoyloxy or b5 3,5-dinitrobenzoyloxy, and so on.

The term "sugar" is used herein to refer, in particular, to mono-, di-, or tri-saccharides and their acylated forms. Without limitation, such sugars can be, for example, a mono-aldose or a ketose having 5 or 6 carbon atoms, preferably in the cyclic furanose or pyranose form, as well as in the eye form of the dD anomer, and having O or I optical isomers. Examples of acceptable sugars include glucose, mannose, fructose, galactose, maltose, cellobiose, sucrose, rhamnose, xylose, arabinose, fucose, quinose, apiose, lactose, galactose-glucose, glucose-arabinose, fucose-glucose, rhamnose-glucose, glucose- glucose-glucose, glucose-rhamnose, mannose-glucose, glucose-(rhamnose)-glucose, glucose-(rhamnose)-rhamnose, glucose-(glucose)-glucose, galactose-(rhamnose)-galactose and their acylated (e.g., acetylated ) derivatives.

The first aspect of the present invention 70 C-Keto-5 D-H steroidal sapogenin, the starting material for ethane, which begins with the formation of the desired sapogenin according to the first aspect of the present invention, preferably corresponds to sapogenin with all points of the molecule except the group at position 3. However, the necessary or desired, suitable protecting groups can be applied for reduction and subsequently removed to yield the desired sapogenin.

The term "protecting groups" as used herein refers to groups used to protect active 75 functional groups, for example, hydroxy or carboxy groups, where the latter are desired in the final reaction products to avoid their unwanted participation in the reaction. Generally accepted protective groups can be used in accordance with the standard methodology, for example, in |article T. MU. OSgeep and R. b. M. Muutsiv in "Rgoiesiime SgoiMrv ip Ogdapis Spetivigu" doip MUMPeu and Bopv, 1991; 9). B. M/ MsOtie in "Rgoiesiime Sgotsrv ip Ogdapis Spetivigu"

Riepyt Rgezz, 1973).

A certain amount of reagents was found to have a selective effect in the preparation of smilagenin or epismilagenin, as shown below in Table 1 (the selectivity percentage refers to the components of the crude reaction product). It was found that the use of K, | or M-ZeIesiide F (potassium, lithium or sodium tri-wt-butylborohydride) or the corresponding triphenylborohydride leads to the formation of a D-hydroxyl, such as smilagenin, in a highly stereoselective manner. Application of the less difficult Ge! of lithium triethylborohydride, as a reducing agent, leads to the formation of 3 o-hydroxyl, for example, o epismilagenin, in a highly stereoselective manner. It has also been found that the use of an organoaluminum hydride such as LTBA also leads to the formation of a C o-hydroxyl such as epismilagenin in a highly stereoselective manner. In the stereoselective reduction of 3-keto-5D-H steroidal sapogenins according to the present invention, it was found that it is possible to obtain a molar ratio of the obtained dominant 3-hydroxy steroids to alternative 3-epimers of at least about 10:1, with examples of at least about 15:1. "- - zv co

PAnovie Me nitettto 00000560 sho 0007800000900000000108108000 same 01009904 « o ve0017009509011181 81 o is. tavnieviev at 007800007900000000104000095

I" 1 so sh - s) 20 is Kvvesteyu| 0200000 te0000000001v360000004000000005

Ковевстее 07800000 Мельтеталярофувно 89220006 о ю 60 It was found that low temperatures (for example, about -782С) are not an essential condition for the method according to the present invention. The reduction can usually take place at temperatures from -1002C to 252C, preferably from -402C to 252C, most preferably from about -109C to 102, and accordingly in a solvent selected from TIF, 2-methyltetrahydrofuran (MTHF), toluene, 1 ,4-dioxane, tert-butyl methyl ether and mixtures of these solvents, most preferably - THF. because In a preferred embodiment, 3-keto-5 D-H steroid sapogenin, as a starting reactant,

for example, smilagenone obtained by heterogeneous catalytic hydrogenation of the corresponding di-3-keto steroidal sapogenin, for example, diosgenone.

Such d?-3-keto steroidal sapogenin, for example, diosgenone, which is preferably obtained by oxidation of the corresponding AZ-3-hydroxy steroidal sapogenin, for example diosgenin, to obtain an o,p-unsaturated ketone. It will be noted that the direct reduction of diosgenin, using palladium or coal as a catalyst, gives the predominant 5o-product - tigogenin.

Marker |Magkeg ei ai, U. At. Spent boss, 62, 2525 (1940)| found that the reduction of diosgenone to smilagenone could be achieved over a palladium-barium sulfate catalyst in ether solution under a hydrogen atmosphere. Low 70 concentration (500 volumes; normal technological volumes are in the range of 5-30 volumes) and high loading of the catalyst (100095; normal loading of the catalyst is in the range of 1-2095) make the described process practically impossible and not economically rational for industrial use. In addition, ether is not suitable for industrial use due to safety concerns.

Other scientists have also investigated the reduction of diosgenone to smilagenone. Djerasi reduced diosgenone (10g) in 75% ethanol (450ml) on previously reduced 1095 Pa-C (0.8g) at atmospheric pressure. Crude smilagenon was isolated by precipitation with water and recrystallized from chloroform/methanol into the final product of the reaction - pure smilagenon (7.2 g, 7290) with a melting point of 179-1832С. The product of the reaction did not change when the reaction proceeded in the presence of potassium hydroxide (KH). An analytically pure sample melted at a temperature of 186-1882С

Uazpip apa KozepKgap, U. At. Spent os, 74,422 (1952)). This process is complicated by the low solubility of diosgenone in ethanol.

While studying the pregnane series, Suvorov found that pyridine affects the result of hydrogenation reactions.

Of course, 1095 palladium on calcium carbonate (Ra-CaCO»5) was chosen as the catalyst in this work. In these cases, it was found that the selectivity significantly exceeded the selectivity of the reactions taking place in alcohol solvents, even with the addition of caustic

The research discussed in this paper involved quenching with dilute hydrochloric acid and extracting the He) reaction product with chloroform. The organic extract was washed with dilute hydrochloric acid, 895% aqueous sodium bicarbonate solution and water until neutral litmus reaction. This method results in a large amount of aqueous waste containing pyridine and halide solutions requiring disposal, increasing production costs. Shk

Irysmetov showed that high selectivity can be achieved in the reduction of diosgenone to smilagenon. In "In this work, diosgenone (1g) was hydrogenated at 595 Ra-CaSoO" (1g) in pyridine (ZOml) at atmospheric pressure. After filtration, to remove the catalyst, and evaporation of the solvent, the sediment was crystallized from alcohol to obtain a solid substance with a melting point of 209-211 20. The final products of the reaction are not given. Acad. Mak Ka. ZBK, Zeg. Kpit., 2.47 (19823). This work has a disadvantage in industrial production - high loadings of the catalyst (100905) and diluted solutions. Pyridine is a toxic solvent and is more widely used in stoichiometric quantities as a reagent to aid acid removal in industrial production.

In the Ipatent of Great Britain Mo736818)| the claimed reduction of 3-keto-steroids to 5o-H steroids on a palladium catalyst in the presence of an inorganic base and in an anhydrous environment. The best solvent is 0/2) with methanol, and the best base is potassium hydroxide. Diosgenone is not given as an example. Diosgenone has been found to be poorly soluble in alcohols (especially ethanol), making the process environment very dilute. Such a method requires an extraction procedure. (UK Patent Mo763301) refers to the favor of an alkali (such as sodium or potassium hydroxide) in Increasing the amount of 5D -H of the product in the reduction of 3-keto-l"steroids. The formula of this patent claims the use of triethylamine in this context. Selected solvents include ethanol, ether, ethyl acetate, and methylcyclohexane, with 1,4-dioxane being the preferred solvent. - It has been found that the use of palladium on a base such as barium sulfate (Ra-Vabo)) or calcium carbonate - (Ra-CasSo)”) in an acceptable solvent provides an economical and acceptable method. Techniques in which 5p use commercially effective concentrations and low loadings of catalysts are disclosed. In addition, it was found that the reduced forms of these catalysts are more selective than the non-reduced forms, as shown below in Table 2.

Resasozshute 18121011 60 596 Ra/graphite (opypvzop Maikpeu type 450) and 1095 Ra/C (doppzop Maipeu type 39) are also acceptable catalysts for this process.

Acceptable solvents may be selected from THF, 2-methyltetrahydrofuran, toluene, 1,4-dioxane, ethyl acetate, methyl isobutyl ketone, most preferably THF. These solvents have been found to be more beneficial than pyridine. With b5 these solvents, the process can proceed at a concentration of 17 volumes to 50 volumes, preferably at 3:30 and most preferably at 3:10. The catalyst loading is in the range from 1 to 2595, preferably from 1 to 1095 and most preferably from 1 to 595.

It was found that an increase in pressure led to a decrease in selectivity in the process. The reaction preferably takes place at a hydrogen pressure of 1-5 bar and more preferably at 1-2 bar.

Elevated temperature has also been found to decrease selectivity. The reaction preferably takes place at a temperature of 15-752C, more preferably at 20-502C and most preferably at 20-30260.

THF provides better solubility of diosgenone compared to ethanol and other possible ether-substituted solvents such as diethoxymethane and tert-butyl methyl ether, which implies a higher productivity and greater economic efficiency of the process. This process provides a simpler study compared to working in a 7/0 ethanol/aqueous sodium hydroxide solution.

The study consists in the concentration of the reaction mixture and the isolation of smilagenon. The solvent can be reused.

Solvents effective in purifying smilagenon include cyclohexane, 2-butanone, acetone, 2-propanol, and methanol; examples of these are given in Table C below. initial relationship 12000200 vyv 010 pe NY M PO i Ps EE POS NN NN propanol 0112 |7116o0 vo | lav ot om

A preferred variant of the invention consists in transferring a solution of smilagenon in THF from ethane of the hydrogenation step directly to the stage of reduction according to the first aspect of this invention. This avoids the need to isolate and dry the intermediate smilagenon, saves time and equipment used, and is therefore (o) expected to reduce production costs. It was found that impurities formed in this process (mainly epitigogenin and epismilagenin) can be removed by recrystallization of crude smilagenin.

The second aspect of the present invention is the second aspect of the present invention represents the rearrangement of 3-hydroxy-5D-N steroidal sapogenins and their derivatives into 3-hydroxy-bD-N steroidal sapogenins and their derivatives, such as esters, by stereospecific and inversion. For example, episarsasapogenin can be easily rearranged into a new compound sarsasapogenin - pe benzoate by the action of diisopropylazodicarboxylate, triphenylphosphine and benzoic acid, the so-called reaction

Mitsunobu | Nidpevz, Ogdapis Keasiyopv, 42,337-400 (1992)). Sarsasapogenin benzoate and its preparation, such -

In this way, further features of this invention are made up. Thus, epismilagenin can be converted into the known ester of smilagenin benzoate. The process is not limited to the formation of benzoate esters, but can practically be used to obtain an aliphatic ester, for example, acetate, propionate, p-butyrate, i-butyrate, p-caproate, i- caproate, palmitate, substituted aliphatic, for example, chloroacetate, methoxyacetate, protected amino esters, for example, Bos-aminoglycinate, Bos-aminovalinate, CB7-aminoglycinate, "

SVaA-aminoalinate, or substituted aromatic ethers, for example, chlorobenzoate, nitrobenzoate, tichlorobenzoate y) c, etc. y The synthesis scheme may alternatively involve the preliminary formation of an activated form of C o-5p-sapogenin, such as methanesulfonate (mesylate) or p-toluenesulfonate (tosylate). This activated form may then be an activated anionic salt of the carboxylic acid (e.g., sodium salt, calcium or potassium), in a typical manner for nucleophilic substitution. (ee) Isolation of the resulting compound from the compound obtained according to any aspect of the present invention can be isolated from the reaction mixture by a conventional method. For example, the compound can be isolated by distilling the solvent from the reaction mixture , or, - if necessary, after distillation of the solvent from the reaction mixture, by flooding the residue with water, followed by removal of the water-immiscible organic solvent from the extract. Additionally, the reaction product, if necessary, can be further purified by various well-known methods , such as recrystallization, reprecipitation or various chromatographic methods, especially column chromatography or preliminary thin-layer chromatography.

Examples

The following examples illustrate, without limitation, the synthesis of episarsasapogenin, smilagenin and epismilagenin by selective reduction with stereochemical control. The examples also illustrate stereospecific

F, conversion of Zo-hydroxy-5-D-H sapogenins into 3-hydroxy-5-D-H sapogenins and their derivatives. Example 1

Synthesis of smilagenin from smglagenon with I-ZeIesigide at a temperature of -102С 60 Smilagenon (657g) was dissolved in tetrahydrofuran (4000ml), nitrogen was passed through the solution, and cooled to a solution temperature of about -1090. | -ZeIesigide? (2400ml; 1M in THF) was added over about 50 minutes and stirred for 90 minutes. A solution of citric acid (b00g) in water (2000ml) was gradually added, keeping the temperature below 02C. The mixture was heated to ambient temperature and stirred for 30 minutes. The water layer was separated, extracted with dichloromethane (200000 ml), and the layers were separated. The aqueous layer was extracted with dichloromethane (1500 ml). The mixed organic extracts were washed with water (4000 ml) and dried over Mazo.

The organic extracts were evaporated to dryness and the final product of the reaction was obtained - smilagenin.

Example 2

Synthesis of smilagenin from smilagenon with K-ZeiiIesigidee at a temperature of -1590

K-Zeiesigidef (1600ml; 1M in THF) was added to a solution of smilagenon (500g) in THF (3500ml) at about -159C under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 30 minutes and quenched with an aqueous solution of citric acid (39 g in 1300 ml of water), maintaining the temperature of the solution at about 092C. The mixture was warmed to ambient temperature and the THF was evaporated at atmospheric pressure to form a solid precipitate. The precipitate was filtered and dried using a pump.

The solid was dissolved in dichloromethane (bb0O0ml), dried (M950,) and evaporated to form a white 70 solid, which was recrystallized from isopropyl alcohol (5000ml) to give smilagenin.

Example C

Synthesis of smilagenin from smilagenon with M-Zeiesigidea at a temperature of -782C

M-Zeiesigidee (0O, b4ml, 1M in THF) was added to a solution of smilagenon (20bmg) in THF (1Oml) for 10 minutes at -782C. The mixture was stirred and quenched with 1096 aqueous solution of citric acid (2g in 20ml of water) and the product was extracted with dichloromethane (2x50ml), dried (Ma5O)) and evaporated to obtain a colorless oil. The oil was collected with acetone (200 ml), and water (50 ml) was added. The precipitate was collected by filtration and dried to obtain smilagenin (20Omg, 9795).

Example 4

Synthesis of smilagenon from diosgenone

Diosgenone (500g) was dissolved in THF (2500ml) at 400-459 and placed in an inert nitrogen atmosphere. 590

PpRa-Ba5o, (reduced) (100g) was added; hydrogen was passed through the solution in the flask, and it was stirred in a hydrogen atmosphere for about 6.5 hours. The flask was cooled to room temperature and the catalyst was removed by filtration through celite (50g). The solution was evaporated to obtain the final product of the reaction - crude smilagenon in the form of a solid precipitate. with

The process was repeated, the final products of the two sequences were combined (902.8g) and suspended in cyclohexane (He) (2260ml) at ambient temperature in a nitrogen atmosphere for about 30 minutes. The resulting solid was collected by filtration and dried in a vacuum at a temperature of about 402C overnight to obtain the final product of the reaction - purified smilagenon (749.1g; 75906).

Example 5 She

Synthesis of smilagenon from diosgenone so

Diosgenone (700g) was dissolved in THF (4500ml) and placed in an inert nitrogen atmosphere. The mixture was cleaned with activated carbon (Z5g) and hydrogenated at 595 Ra-Vazo, (reduced) (Z35g) at 252C and a hydrogen pressure of 2.5 bar. --

The catalyst was removed by filtration, and the mixture was thickened to about a quarter of the volume. Water (3000 mL) was added over about 30 minutes, and the resulting solid was filtered off. The solid was washed with methanol

Zo (560ml) and dried in vacuum at 40-5022; to obtain smilagenon (63Z0O0g, 90965). co

Example 6

The degree of hydrogenation and reduction reactions

Diosgenone (500g) was dissolved in THF (2500ml) and placed in an inert nitrogen atmosphere. Added 595 Ra-VazoO, « (reduced) (100g); hydrogen was passed through the solution in the flask and stirred in a hydrogen atmosphere for about 5 hours. The catalyst was removed by filtration through celite (20 g). The precipitate was washed in tetrahydrofuran (100 Oml), and the solution was used in the next step. :z» K-Zeiesigidef (1600ml; 1M in THF) was added to a solution of smilagenon (500g) in THF (3500ml) at about -159C under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 30 minutes and quenched with an aqueous solution of 15% citric acid (39g in 1300ml of water), maintaining the temperature of the solution at about 09C. The mixture was heated to oo ambient temperature, and THF was evaporated at atmospheric pressure to form a solid precipitate. The precipitate was filtered and dried using a pump. - The precipitate was dissolved in dichloromethane (b00O0ml), dried (Ma95O,) and evaporated to obtain a white solid, which was recrystallized from 2-propanol (500O0ml). The solid was recrystallized from acetone (5000 mL). Then it was recrystallized from acetone (3500 ml) and dried at 802 in a vacuum to obtain pure smilagenin (154.5 g). se" Melting point 184.7-187.0 C; |b) 070--73.39; IKumdh 3456.2928, 1451.1376, 1050.979, 896 cm"; EVI-M8 mass/charge 417 |M'Atsk; IN nNMR (SOSIz, ZOOMN?): in particular 5 4.39 (1H, Bg a, U -8H2), 4.10 (1H, Bg c), 3.46 (1H, g ad, U-11H2), 3.39 (1H, i, U-11H2), 0.98 (ZH, c), . 16.43, 17.10, 20.83, 23.86, 26.48, 26.50, 27.75, 28.73, 29.89, 30.24, 31.32,

F! 31.73, 33.46, 3521, 35.21, 36.45, 39.78, 40.24, 40.63, 41.54, 56.41, 62.19, 66.79, 66.98, 80.87, 109.20 ppt; yuyu C 77.9490; H 10.7595 (theoretical value for Co7NadOz: C 77.8490; H 10.64905).

Example 7

The steps of the hydrogenation and reduction reactions were added to a solution of smilagenone (156bg) obtained by the hydrogenation of diosgenone in THF at a temperature of about -109C in a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 30 minutes, warmed to ambient temperature and stirred overnight. The mixture was quenched by adding a mixture of an aqueous solution of citric acid (311g in 380O0ml of water) and dichloromethane (2200ml), while maintaining the temperature of the reaction mixture below 309C. The aqueous phase was separated and re-extracted with dichloromethane (40 Oml). The combined organic extracts were washed with an aqueous solution of citric acid (160 g

2200 ml of water) and boiled until the volume is reduced. 2-Propanol (3300 mL) was added and the mixture was distilled again to about 1/2 volume. Additionally, 1500 ml of 2-propanol was added, and the mixture was distilled to 1/2 volume. The mixture was heated under reflux and cooled. The mixture was further cooled to 0-102C and filtered. The solid substance was dried in a vacuum by heating to 60-652C to obtain smilagenin. The yield of the reaction product was 94, Ohm.

Example 8

Reduction of smilagenon to epismilagenin

Lithium tri-tert-butoxyaluminum hydride (1M in THF, 99ml) was added dropwise to a solution of smilagenon (32.Og, 77.2mmol) in THF (800ml) at a rate at which the temperature was maintained at 14-16°C. Once 70 additions were complete, the mixture was stirred at room temperature for 2 hours. The remaining reducing agent was quenched by careful addition of ammonium chloride solution (30Og in 40O0ml of water). The mixture was filtered and the precipitate was washed with dichloromethane (30 mL). The combined filtrates were evaporated and the residue partitioned between dichloromethane (300 mL) and water (300 mL). The aqueous layer was further extracted with dichloromethane (2x30Oml). The combined organic layers were dried (M950.5) and evaporated to give a white solid (25.7g). Then 75 was recrystallized from acetone (1250ml), and the resulting substance (19.0g) was dried in vacuo by heating to 402 overnight. Next, the solid was purified by heating the suspension in acetone (1425 ml), dried in a vacuum by heating to 4029 overnight. It was then finally purified by recrystallization from 2-propanol (ZOOmL), and the solution was hot filtered to remove any inorganic matter. The filtrate was cooled, the solid was filtered off and dried at 602C in a vacuum by heating overnight to obtain epismilagenin (9.05).

Melting point 223-227 2С; (91022--649(c-5 dI"; SNO"); IKumdh "KVg) 3392,2937, 1451, 1369,1051, 982,864

CM-1; E8I-M5 mass/charge 417 (МН117; IN nMR (SOS3, 300 МН): in particular 5 4.40 (1Н, Bg а, У-8Н2), 3.62 (1Н, septet, У-10, 10, 5 ,5H2), 3.48 (1H, Bg ad, o0-11H2), 3.37 (IN, 5, 9-11H2), 0.97 (ЗН, а, 9-7Н), 0.95 (ЗН, 5), c 0.79 (ZN, a, 9-7Nl), 0.75 (ZN, c) ppt; 132 NMR (SOCI3, 75 MN?) in particular: 5 14.91, 16.85, 17.55 , 20.99, 23.78, 27, 08.27, 49.30, 68.31, 75.32, 18, 35.09, 35.75, 35.85, 40.62, 40.91, 41 .04, 41.99, 42.39, 56.74, 62, 59, o 67.23, 72.10, 81.30, 109.64 ppm; С 77.7790; C27NalOz: C 77.8490; H 10.6496).

Example 9

Synthesis of smilagenin benzoate from epismilagenin so

A solution of diisopropylazodicarboxylate (0.81g, 4.0mmol) in anhydrous THF (2ml) was added to a stirred solution of epismilagenin (0.83g, 2.00mmol), triphenylphosphine (1.05g, 4.00mmol) and benzoic acid (0.49g, 0.00mmol). Shk 4, Ommol) in anhydrous THF (20 ml). The reaction mixture was stirred at room temperature and monitored by thin-layer chromatography. After two hours, all starting substances reacted. The solvent was removed under vacuum, the residual product was dissolved in ether (30 ml), and the solution was washed with a saturated aqueous solution of sodium bicarbonate (25 ml). The organic layer was dried at М950О and passed through a silica filter, the 00 filter was washed with ether. The combined washings and filtrate were evaporated in vacuo to give smilagenin benzoate as a white solid.

Example 10 «

Synthesis of sarsasapogenin benzoate from episarsasapogenin

A solution of diisopropylazodicarboxylate (0.81g, 4.0mmol) in anhydrous THF (2ml) was added to a stirred solution of episarsasapogenin (0.83g, 2.0mmol), triphenylphosphine (1.05g, 4.0mmol) and benzoic acid (0 ,49Hg, ts 4, Ommol) in anhydrous THF (20ml). The reaction mixture was stirred at room temperature and monitored by thin-layer chromatography. After two hours, all starting substances reacted. The solvent was removed under vacuum, the residual product was dissolved in ether (30 mL), and the solution was washed with saturated aqueous sodium bicarbonate solution (25 mL). The organic layer was dried over Mo5O), and passed through a silica filter, (ee) the filter was washed with ether. The combined washings and filtrate were evaporated in vacuo to give sarsasapogenin benzoate as a white solid.

Melting point 173-1752С; "H NMR (500МН2, СОСИ"): 5 0.77 (ЗН, в, 18-СН»У), 1.00 (ЗН, а, 9-6.7Н2, 21-СН»), -y 1, 04 (ЗН, в, 19-СНУ), 1.08 (ЗН, а, 9-7.0Н2, 27-СН»), 1.1-2.1 (27Н, complex multiplet, aliphatic), 3.31 (1H, syu 50 r, a, 9-10.9n7, 26-OSNN), 3.96 (1H, bBg, aa, 9-10.9, 2.0n27, 26-OSNN), 4.42 (1H , t, 16-OSN), 5.34 (1Н, рБбг, в,

H-3), 7.44 (2H, p, 6 9-7.6H7, aromatic H), 7.55 (1H, B, Her, 9-7.6H2, aromatic H), 8.05 (1H, Bg, a, c» U-7,6H2, aromatic H) ppt; C NMR (125.6MH2, SOSiO): δ 14.56, 16.28, 16.71, 21.17, 24.28, 25.41, 26.01, 26.19, 26.69, 27.31 , 31.02, 31.33, 31.98, 35.37, 35.57, 37.92, 40.28, 40.48, 40.91, 42.36, 56.63 (0-14), 62.33 (0-17), 65.36 (0-26), 71.54 (0-3), 81.22 (0-16), 109.94 (0-22), 128.54 (aromatic C), 129.73 22 (aromatic C), 131.39 (aromatic C), 132.9 (aromatic C), 166.13 (carbonyl) ppt. (FI Example 11

Synthesis of episarsasapogenin from sarsasapogenone o A solution of lithium tri-tert-butoxyaluminum hydride in THF (1M, 41.71kg) was added (over about 2 hours) to a stirred solution of sarsasapogenone (17.38kg) in anhydrous THF (about 7Okg) at a temperature of -23 to 60,309 in dry nitrogen. The flow line was washed with THF and the mixture was shaken at a temperature from -23 to -302C for

From hours The resulting solution was carefully quenched with an aqueous solution of sodium sulfate (5.67 kg in 28.67 kg of water).

Inorganic salts were removed by filtration and washing with THF (184 kg). Water (63.18Kkg) was added, and the bulk of the THF was removed by distillation. Additionally, 126.44 kg of water was added, and the final product was isolated by filtration. The final product of the reaction was washed with water (2 x 17.38 kg) and acetone (4 x 13.7 kg), dried at 35-40 to obtain episarsasapogenin (14.48 kg).

The foregoing broadly describes the present invention without limitation.

Changes and modifications resulting from professional experience in the field should be included within the scope of this application and any related, subsequent patents.

Claims (38)

The formula of the invention 1. The method of stereospecific production of 3-hydroxy-5V-H steroid sapogenin or its derivative, which includes the reduction of 3-keto-58-H steroid sapogenin using a reducing agent that includes a hindered organoborane or organo-aluminum hydride. 2. The method according to claim 1, which differs in that the reducing agent is a hindered organoborane in which the organic groups contain more than two carbon atoms, and the resulting sapogenin is mainly 3B-hydroxy-58-H-sapogenin. C. The method according to claim 2, which differs in that the hindered organoborane is selected from reducing agents: trialkyl or triaryl borohydrides of alkali metals. 4. The method according to any of the previous items, which is characterized by the fact that the hindered organoborane is selected from lithium tri-tertiary-butylborohydride, potassium tri-tertiary-butylborohydride, sodium tri-tertiary-butylborohydride, lithium trisiamylborohydride, potassium trisiamylborohydride, sodium triphenylborohydride and lithium triphenylborohydride. 5. The method according to claim 4, which differs in that the hindered organoborane is lithium tri-tert-butylborohydride. b. The method according to claim 1, which differs in that the organoaluminum hydride is lithium tri-tert-butoxyaluminum hydride. 7. The method according to any of the previous items, which is characterized in that the molar ratio of the obtained dominant sapogenin to the alternative 3-epimer is at least about 10:1. 8. The method according to claim 7, characterized in that the ratio is at least about 15:1. high school 9. The method according to any of the previous items, which is characterized by the fact that the organic solvent is selected from tetrahydrofuran, toluene, tert-butyl methyl ether, diethoxymethane, 1,4-dioxane, (o) 2-methyltetrahydrofuran and any mixture thereof . 10. The method according to claim 9, which is characterized by the fact that the organic solvent mainly contains tetrahydrofuran. 11. The method according to claim 9, which differs in that the organic solvent mainly contains toluene. so so 12. The method according to claim 9, which differs in that the organic solvent mainly contains 1,4-dioxane. 13. The method according to claim 9, which differs in that the organic solvent mainly contains 2-methyltetrahydrofuran. "- 14. The method according to any of the previous clauses, which differs in that the desired sapogenin is a compound of the general formula: ro H so vv where Ki Ko, Kz, Ka, Kv, Kv, K7, Ka and Ko are independently of each other H, C..4 alkyl, OH or OK, where K is Sv.12 - aryl or C. alkyl , or K5 and Ke together can be -O (carbonyl) or a protected carbonyl group, - the stereochemistry of the carbon atom in position C can be either K or 5, and Ko is OH, an O-bonded hydrocarbon group, or a group of any organic ether. at 15. The method according to claim 14, which differs in that sapogenin is selected from sarsasapogenin, smilagenin and their HA) esters. 16. The method according to any of the previous items, which is characterized by the fact that 3-keto-58-H steroid sapogenin, which is used as a starting reactant, is obtained by heterogeneous catalytic hydrogenation of the corresponding d"-3-keto steroid sapogenin for the conversion of l7 -3-keto of steroid sapogenin mainly into the mentioned 5B-H-3-ketone 17. The method according to claim 16, which is characterized by the fact that the heterogeneous catalytic hydrogenation is performed using hydrogen and a palladium catalyst in an organic solvent. 18. The method according to claim 17, which is characterized by the fact that a palladium-based catalyst is used. 6o0 19. The method according to any one of claims 16-18, characterized in that the AI-8-keto steroid sapogenin is diosgenone. 20. The method according to claim 19, which differs in that diosgenone is obtained by oxidation of diosgenin. 21. The method according to any of claims 1-20, which differs in that the previously obtained sapogenin is converted into the form of its prodrug or into another physiologically acceptable form. 22. The method of rearrangement of ЗА-hydroxy-58-Н steroidal sapogenins and their derivatives into ЗВ-hydroxy-58-Н 65 steroidal sapogenins and their derivatives, which includes the reaction of the 3-hydroxy-activated derivative of ЗА-hydroxy-58-Н steroidal sapogenin with a nucleophilic reagent according to conditions favorable for nucleophilic substitution with inversion at position 3, with optional subsequent placement of the 3-substituent as necessary. 23. The method according to claim 22, which is characterized by the fact that the reaction is performed according to the Mitsunobu reaction scheme for obtaining the ester derivative and 3B-hydroxy-58-H steroidal sapogenin. 24. The method according to claim 22, which is characterized by the fact that the activated sapogenin derivative is an organic sulfonated derivative. 25. The method according to any of claims 22-24, which is characterized by the fact that the 3-hydroxy-activated derivative of ЗА-hydroxy-58-Н steroid sapogenin is obtained by reducing 3-keto-58-Н steroid sapogenin using a reducing agent that includes a difficult organoborane, including organic groups having up to two /o carbon atoms or organoaluminum hydride, with further conversion of the obtained ЗА-hydroxy-58-Н steroidal sapogenin into its З-hydroxyactivated derivative. 26. The method according to claim 25, which differs in that the organoaluminum hydride is lithium tri-tert-butoxyaluminohydride (LTBA). 27. The method according to claim 26, which differs in that the organoborane is triethylborohydride. 28. The method according to one of claims 25-27, which differs in that the recovery takes place as specified in claims 7-14. 29. The method according to any one of claims 25-28, which is characterized by the fact that ЗА-hydroxy-58-Н steroidal sapogenin and its derivatives, obtained in the reduction, are selected from episarsasapogenin, epismilagenin and their esters. 30. The method according to any one of claims 22-29, which is characterized in that the 3B-hydroxy-58-H steroidal sapogenin and its derivatives obtained in the transformation are selected from sarsasapogenin, smilagenin and their esters. 31. The method according to any of claims 25-30, which is characterized by the fact that 3-keto-5B8-H steroidal sapogenin, used as a starting reactant, is obtained by heterogeneous catalytic hydrogenation of the corresponding 1-3-keto steroidal sapogenin for conversion L7-3-keto of steroid sapogenin mainly into the mentioned 5B-H-3-ketone. 32. The method according to claim 31, which differs in that the heterogeneous catalytic hydrogenation is performed as specified in the aqueous SU from claims 17-19. at 33. The method according to any one of claims 31 and 32, which is characterized in that the diI-3-keto steroid sapogenin is diosgenon, which is obtained by oxidation of diosgenin. 34. The method according to any one of claims 22-33, which differs in that the previously obtained sapogenin is converted into the form of its prodrugs or into another physiologically acceptable form. (ze) 35. The method of obtaining smilagenin, which includes the catalytic hydrogenation of diosgenone followed by the recovery of the obtained 3-keto-58-H steroidal sapogenin using a hindered organoborane. 36. The method according to claim 35, which differs in that the previously obtained sapogenin is converted into the form of its 7 prodrugs or into another physiologically acceptable form. - 37. The method of obtaining epismilagenin, which includes the catalytic hydrogenation of diosgenon followed by the recovery of the obtained 3-keto-58-H steroid sapogenin using organoaluminum hydride. (uh) 38. The method according to claim 37, which differs in that the previously obtained sapogenin is converted into the form of its prodrugs or into another physiologically acceptable form. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 20, 10.12.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. ;" (ee) - - o 50 syu» F) ime) 60 b5