RU2309159C2 - Method for production of 4,17(20)-z-pregnadiene-3,16-dione, method for compound production - Google Patents

Abstract

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to improved method for production of 4,17(20)-E-pregnadiene-3,16-dione (E-guggulsterone) of formula III

and 4,17(20)-Z-pregnadiene-3,16-dione (Z-guggulsterone) of formula IV

including oxidation of compound of formula II

, wherein C-OH or =O; ----- is optional double bond with pyridinium chlorochromate, pyridinium dichromate etc to produce 4,17(20)-E-pregnadiene-3,16-dione of formula III followed by conversion thereof by photochemical, thermochemical reaction or reaction in presence of acidic catalyst. Compounds of formulae III and IV effectively decrease increased low density lipoprotein levels and high cholesterol levels.

EFFECT: improved method for production of 4,17(20)-Z-pregnadiene-3,16-dione.

8 cl, 46 ex, 9 dwg

Description

The present invention relates to a method for producing 4.17 (20) -pregnadiene-3.16-dione (hereinafter referred to as guggulsterone), which effectively reduces elevated low density lipoproteins (LDL) and high cholesterol and increases low lipoproteins high density (HDL), to a method for producing the Z-isomer of guggulsterone from the E-isomer and to a method for producing a compound of formula (II), an intermediate to obtain the above compound (III).

Guggulsterone is extracted from the Indian Guggul tree (botanical name Commiphora mukul ) and traditionally used to treat hyperlipidemia, it is also known as an effective antagonist of the farnesoid orphan receptor (FXR), which regulates cholesterol metabolism (Nature, 2002, June, 411; Science, 2002, May , 1703). Usually, the E-type or Z-type of guggulsterone is used as a lipid-lowering drug, which is obtained by extraction of the guggul tree resin, if necessary, followed by purification by HPLC, etc. As shown in the diagram below, the ketone and acetate groups of 16-dehydropregnone acetate (1) are reduced with lithium aluminum hydride (LiAlH ₄ ) to give 5.16-pregnadiene-3β, 20-diol (2), which reacts with acetic anhydride and p-toluenesulfonic acid to give a mixture of 5.17 (20) -trans-pregnadiene-3β, 16β-diacetate and 5.17 (20) -trans-pregnadien-3β, 16α-diacetate (3). The resulting mixture is reacted with potassium hydroxide in methanol to give a mixture of 5.17 (20) -trans-pregnadiene-3β, 16β-diol and 5.17 (20) -trans-pregnadiene-3β, 16α-diol (4), which is oxidized aluminum isobutoxide or aluminum phenoxide, obtaining a mixture of stereoisomers (Z: E is approximately 8: 2) guggulsterones.

Although it is known that the above compound (5), obtained by the method described in EP 0447706 A1, has good efficiency, the method for its industrial production is not satisfactory and economically disadvantageous. In other words,

1) the starting material, 16-dehydropregnalone, does not belong to widely available steroids and, therefore, is not suitable for industrial use;

2) when moisture is exposed to lithium aluminum hydride (LiAlH ₄ ) used in the first reduction stage, hydrogen gas is formed, which can lead to an explosion, and, therefore, its use on an industrial scale is very dangerous;

3) the acetic acid used as a solvent in the second reaction is difficult to remove after completion of the reaction, and, in addition, the reaction time, 72 hours, is too long;

4) in the third stage of the reaction, methanol is heated under reflux in the presence of potassium hydroxide for a relatively long time, for 6 hours;

5) the yield in the third stage of the reaction is 114%, however, the yield of the final product, guggulsterone, is not indicated in the patent description;

6) the synthesis method described in the above patent is not reliable, since the analysis data of guggulsterone and its intermediate are not given in the patent description.

In accordance with the method described in J. Org. Chem., 1964, 29, 1142, 16α, 17α-epoxypregnenolone is reacted with hydrazine of 85% purity at 190 ° C for 5.5 hours to form a diol intermediate, which is a mixture of trans and cis isomers. Since the yield of the diol compound is 21.7%, the final product, guggulsterone, cannot be obtained on an industrial scale.

In addition, the method disclosed in J. Org. Chem., 1964, 29, 1142, has the following disadvantages.

1) Since the yield of the obtained diol compound (8a) is 21.7%, this method is not suitable for industrial use.

2) The diol compound (8a) is obtained as an optically inactive mixture, therefore, additional isolation is required. In addition, the final product has low efficiency as a medicine or food product.

In light of the foregoing, there is a need in the art for a new, simpler and cheaper method for producing individual E-type or Z-type guggulsterones.

The objective of the present invention is an economical method for producing guggulsterol, individual guggulsterone E-type (III) and individual guggulsterone Z-type (IV) in high yield, in a short reaction time, using readily available and cheap starting material.

Based on the foregoing, the authors of the present invention conducted an extensive study on the synthesis of guggulsterone. So, they found that it is possible to selectively obtain a diol compound with a yield of 91% by reacting 16.17-epoxypregnenolone with hydrazine of 95% purity at 160 ° C for 2 hours. As a result, they developed effective methods for preparing the compound represented by the following formula (II) from a known steroid represented by the following formula (I), as well as simple and economical methods for the synthesis of guggulsterones represented by the following formulas (III) and (IV).

where A represents a hydroxyl group (—OH) or an oxo group (= O); B represents a hydroxyl group (—OH), an oxo group (= O) or a methyl ketone group (—C (O) CH ₃ ); C represents a hydroxyl group (—OH) or an oxo group (= O); n denotes the number of oxygen atoms, 0 or 1, and the dashed line indicates the presence of a double bond at position C-4 (hereinafter referred to as Δ ⁴ ) or C-5 (hereinafter referred to as Δ ⁵ ).

Description of the preferred embodiment

A compound of formula (III), an object of the present invention, can be obtained by oxidizing a compound of formula (II), and a compound of formula (IV) can be obtained by isomerizing a compound of formula (III). The above preparation method is explained after the description of the preparation method of the compound of formula (II) using the compound of formula (I) as the starting material.

I. Synthesis of a compound of formula (II)

I-1. The synthesis of a compound of formula (II-A) from 4-androsten-3,17-dione (IA) of formula (I), where A and B respectively represent an oxo group (= O), n is 0, and Δ ⁴

The compound of formula (IA) is treated with 1,2-ethanedithiol to protect only the ketone group at position C-3, to obtain the compound of formula (IA-1), which is subjected to the Wittig reaction on the ketone group at position C-17, to obtain a compound of formula (IA-2). The compound of formula (IA-3) is obtained after deprotection of the ketone group at position C-3 of the above compound of formula (IA-2). The compound of formula (IA-3) is oxidized by reaction with selenium dioxide (SeO ₂ ) to introduce an alcohol group at position C-16, and as a result, guggulsterol is presented, which is represented as a compound of formula (II-A).

Scheme 1

[Step A] Preparation of a compound of formula (IA-1)

A compound of formula (I-A-1) can be prepared by reacting a compound of formula (I-A) with alkanedithiol in a solvent in the presence of an acid catalyst.

As a solvent in this reaction, dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, acetonitrile, tetrahydrofuran, toluene and glacial acetic acid can be used. These solvents can be used individually or as a mixture of two or more solvents. Among these compounds, dichloromethane and glacial acetic acid are particularly preferred.

As alkanedithiol, which protects the selectively conjugated group at position C-3, 1,2-ethanedithiol and 1,3-propanedithiol, preferably 1,2-ethanedithiol, can be used.

As the Lewis acid, boron trifluoro-etherate (BF ₃ · Et ₂ O), zinc iodide (ZnI ₂ ), tellurium chloride (TeCl ₂ ), magnesium iodide (MgI ₂ ) and p-toluenesulfonic acid (TsOH) can be used. Among them, BF ₃ · Et ₂ O and p-toluenesulfonic acid are particularly preferred. The amount of Lewis acid used in this reaction is typically from 0.1 to 2.0 equivalents relative to the amount of alkanedithiol, preferably from 0.5 to 1.0 equivalent.

The reaction temperature depends on the solvent used. However, the reaction is preferably carried out at a temperature of from -10 to 80 ° C, more preferably from 0 to 25 ° C. The reaction time, in turn, depends on the reaction temperature and the solvent used. However, the reaction is preferably carried out over a period of from 30 minutes to 12 hours, more preferably less than 4 hours.

[Step B] Preparation of a compound of formula (IA-2)

To obtain a compound of formula (IA-2), preferably a compound of formula (IA-1) is reacted with ethyltriphenylphosphonium halide (Ph ₃ P ⁺ CH ₂ CH ₃ X ^- ) in a non-aqueous solvent in the presence of a strong base.

As a non-aqueous solvent, diethyl ether, tetrahydrofuran, hexane, heptane, methanol, ethanol, dimethyl sulfoxide, benzene, toluene and xylene can be used. These solvents can be used individually or as a mixture of two or more solvents. Among these compounds, diethyl ether and tetrahydrofuran are particularly preferred.

Ethyl triphenylphosphonium halide in the Wittig reaction can be used ethyltriphenylphosphonium chloride (Ph ₃ P ⁺ CH ₂ CH ₃ Cl ^- ), ethyl triphenylphosphonium bromide (Ph ₃ P ⁺ CH ₂ CH ₃ Br ^- ) and ethyl triphenylphosphonium iodide (Ph ₃ P ⁺ CH ₂ CH ₃ I ^- ). Among these compounds, ethyltriphenylphosphonium bromide and ethyltriphenylphosphonium iodide are particularly preferred.

The strong base used in the Wittig reaction includes lithium hydride, sodium hydride, potassium hydride, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, sodium methoxide, sodium ethoxide or potassium tert-butoxide. Among these compounds, n-butyllithium and potassium tert-butoxide are particularly preferred.

The amount of base used to prepare the ylide is generally from 1.0 to 4.0 equivalents with respect to ethyl triphenylphosphonium halide, preferably from 1.0 to 1.5 equivalents.

The reaction temperature varies depending on the type of solvent used, however, usually it is in the range from -10 to 120 ° C. If ethyltriphenylphosphonium halide interacts with a strong base in the presence of an anhydrous solvent to form ylide, the reaction is carried out at a temperature of from -10 to 20 ° C, if compound (IA-1) is used in the Wittig reaction, the reaction is carried out at a temperature in the range from -10 to the boiling point of the solvent used, preferably from -10 to 20 ° C., if the solvent is tetrahydrofuran.

The reaction time, in turn, depends on the reaction temperature and the solvent used. However, the reaction is preferably carried out over a period of from 30 minutes to 1 day, more preferably less than 2 hours.

[Step C] Preparation of a compound of formula (IA-3)

The compound of formula (I-A-3) can be obtained by deprotecting the ketone group at the C-3 position of the compound of formula (I-A-2).

Solvents suitable for the deprotection reaction include distilled water, acetone, chloroform, dichloromethane, acetonitrile, tetrahydrofuran and glacial acetic acid. These solvents can be used individually or as a mixture of two or more solvents. Among these compounds, tetrahydrofuran and glacial acetic acid are particularly preferred.

Reagents such as silver nitrate (AgNO ₂ ), N-bromosuccinimide (NBS), iodine and selenium dioxide (SeO ₂ ) can be used to remove the protective group. These reagents can be used individually or as a mixture of two or more reagents. Among these compounds, silver nitrate with iodine and selenium dioxide are particularly preferred.

The amount of reagent required to remove the protective group depends on the reagent used. However, preferably 0.5 to 3.0 equivalents are used with respect to the amount of the compound of formula (I-A-2), preferably 0.5 to 1.5 equivalents.

The reaction temperature depends on the solvent and reagent used. However, the reaction is preferably carried out at a temperature of from -10 to 100 ° C, more preferably from 10 to 65 ° C. The reaction time, in turn, depends on the reaction temperature and the type of reagent used, however, as a rule, it is in the range from 30 minutes to 1 day, more preferably it is less than 3 hours.

[Stage D] Obtaining guggulsterol of the formula (II-A)

Guggulsterol of formula (II-A) can be prepared by reacting a compound of formula (IA-3) with selenium oxides (SeO ₂ ) and hydrogen peroxide in a solvent.

The amount of selenium dioxide is usually in the range from 0.1 to 2.0 equivalents with respect to the amount of the compound of formula (I-A-3), preferably from 0.25 to 1.0 equivalent.

As peroxides, hydrogen peroxide, tert-butyl peroxide, N-methylmorpholine N-oxide (NMO) or pyridine N-oxide (C ₅ H ₅ NO) can be used. Among them, tert-butyl peroxide is particularly preferred. The amount of hydrogen peroxide is usually from 0.5 to 3.0 equivalents with respect to the amount of the compound of formula (IA-3), preferably from 1.0 to 2.0 equivalents.

In this method, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, pyridine, acetonitrile, acetone, ethyl acetate, tetrachloroethane, chloroform and dichloromethane can be used as aprotic polar solvents. As ethers, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether can be used. As aromatic hydrocarbons, benzene, toluene and xylene can be used. Aprotic polar solvents and ethers are preferred. More specifically, it is preferable to use dichloromethane and dioxane.

The reaction temperature depends on the solvent used. However, the reaction is preferably carried out at a temperature of from -10 to 80 ° C, more preferably from 10 to 30 ° C. The reaction time, in turn, depends on the reaction temperature and the solvent used, however, the reaction is preferably carried out over a period of 30 minutes to 12 hours, more preferably less than 2 hours.

I-2. Synthesis of a compound of formula (II-B) from 5-androsten-3-ol-17-one [DHEA (IB)] of formula (I), where A is a hydroxyl group (-OH), B is an oxo group (= O), n is 0, and Δ ^{5 is} present

The compound of formula (IB-1) can be obtained by carrying out the Wittig reaction on the ketone group at position C-17 of the compound of formula (IB), without protecting the alcohol group at position C-3, as shown in Scheme 2 below. The compound of formula (II- B) can be obtained by reacting a compound of formula (IB-1) with selenium dioxide (SeO ₂ ), as a result of which an alcohol group is introduced at position C-16.

Scheme 2

[Step E] Preparation of a compound of formula (I-B-1)

To obtain a compound of formula (IB-1), it is preferable to react the compound of formula (IB) with ethyltriphenylphosphonium halide (Ph ₃ P ⁺ CH ₂ CH ₃ X ^- ) in a non-aqueous solvent in the presence of a strong base, without protecting the alcohol group at position C-3 .

As a non-aqueous solvent, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, benzene, toluene and xylene can be used. These solvents can be used individually or as a mixture of two or more solvents. Among these compounds, tetrahydrofuran and dimethyl sulfoxide are particularly preferred.

Ethyl triphenylphosphonium halide in the Wittig reaction can be used ethyltriphenylphosphonium chloride (Ph ₃ P ⁺ CH ₂ CH ₃ Cl ^- ), ethyl triphenylphosphonium bromide (Ph ₃ P ⁺ CH ₂ CH ₃ Br ^- ) and ethyl triphenylphosphonium iodide (Ph ₃ P ⁺ CH ₂ CH ₃ I ^- ). Among these compounds, ethyltriphenylphosphonium bromide and ethyltriphenylphosphonium iodide are particularly preferred.

As a strong base, lithium hydride, sodium hydride, potassium hydride, n-butyl lithium, sec-butyl lithium, t-butyl lithium, sodium ethoxide and potassium t-butoxide can be used. Among these compounds, sodium hydride, n-butyl lithium and potassium tert-butoxide are particularly preferred.

The amount of base used to prepare the ylide is typically from 1.0 to 4.0 equivalents with respect to ethyl triphenylphosphonium bromide, preferably from 1.0 to 1.2 equivalents.

The reaction temperature varies depending on the type of solvent used, however, the reaction is preferably carried out at a temperature of from -10 to 120 ° C. If ethyltriphenylphosphonium bromide reacts in the presence of a strong base in a non-aqueous solvent to form ylide, the reaction is preferably carried out at a temperature of from -10 to 20 ° C, if compound (I-B) is involved in the Wittig reaction, the reaction is carried out at a temperature in the range from -10 ° C to the boiling point of the solvent used. Preferably, the reaction is carried out at a temperature of from 25 to 40 ° C, if the solvent is tetrahydrofuran, and from 25 to 80 ° C, if the solvent is dimethyl sulfoxide.

The reaction time, in turn, depends on the reaction temperature and the solvent used, however, as a rule, it is in the range from 30 minutes to 1 day, more preferably it is less than 2 hours.

[Step F] Preparation of a compound of formula (II-B)

A compound of formula (II-B) can be prepared by reacting a compound of formula (I-B-1) with selenium oxides (SeO ₂ ) and hydrogen peroxide in a solvent.

The amount of selenium dioxide (SeO ₂ ) is usually in the range from 0.1 to 3.0 equivalents with respect to the amount of the compound of formula (I-B-1), preferably from 0.5 to 1.5 equivalents.

As peroxides, hydrogen peroxide, tert-butyl peroxide, N-methylmorpholine N-oxide and pyridine N-oxide can be used. Among these compounds, tert-butyl peroxide is particularly preferred. The amount of hydrogen peroxide is typically from 0.5 to 4.0 equivalents with respect to the amount of the compound of formula (IB-1), preferably from 1.0 to 2.0 equivalents.

In this reaction, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, pyridine, acetonitrile, acetone, ethyl acetate, tetrachloroethane, chloroform and dichloromethane can be used as aprotic polar solvents. As ethers, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether can be used. As aromatic hydrocarbons, benzene, toluene and xylene can be used. Aprotic polar solvents and ethers are preferred. More specifically, dichloromethane and dioxane are preferred.

The reaction temperature depends on the type of solvent used, however, the reaction is usually carried out at a temperature of from -10 to 80 ° C, preferably from -10 to 10 ° C. The reaction time, in turn, depends on the reaction temperature and the type of solvent used, however, the reaction is usually carried out over a period of 30 minutes to 12 hours, more preferably less than 4 hours.

I-3. Synthesis of a compound of formula (II-A) from 5-androsten-3-ol-17-one [DHEA (IB)] of formula (I), where A is a hydroxyl group (-OH), B is an oxo group (= O), n is 0, and Δ ^{5 is} present

A compound of formula (IB-1) can be obtained by carrying out the Wittig reaction on a ketone group at position C-17 of a compound of formula (IB), without protecting the alcohol group at position C-3, followed by oxidation with pyridinium chlorochromate (PCC) to give a compound of formula ( IB-2) with a ketone group in position C-3. The double bond of the compound of formula (IB-2) is displaced in the presence of a base to give a compound of formula (IB-3), which is then reacted with selenium dioxide, whereby an alcohol group is introduced into position C-16, and a compound of formula (II- A) guggulsterol.

Scheme 3

[Step G] Preparation of a compound of formula (IB-2)

A compound of formula (IB-2) can be prepared by reacting a compound of formula (IB-1) with an oxidizing agent.

In this method, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent and Swern oxidizing reagent (DMSO + ClCOCOCl) can be used to oxidize the secondary alcohol group at position C-3 to the ketone group. Pyridinium chlorochromate is preferred.

The solvent used depends on the type of oxidizing agent. Preferably, dichloromethane is used with pyridinium chlorochromate (RCC), N, N-dimethylacetamide with pyridinium dichromate (PDC), acetone with Jones reagent, and dichloromethane with Swern oxidizing reagent.

The amount of oxidizing reagent depends on its type. The amount of chromium-containing oxidizing reagent is typically from 1.0 to 5.0 equivalents relative to the amount of the compound of formula (I-B-1), preferably from 1.2 to 2.0 equivalents.

In the Swern oxidation reaction, the amount of dimethyl sulfoxide used to produce the oxidizing reagent is preferably 1.0 to 3.0 equivalents with respect to the amount of the compound of formula (IB-1), and the amount of oxalyl chloride is preferably 1.0 to 1, 5 equivalents with respect to the amount of the compound of formula (I-B-1).

The reaction temperature depends on the type of oxidizing reagent, but usually it is in the range from -78 to 30 ° C. Preferably, in the case of a reaction using a chromium-containing oxidizing reagent, the temperature is in the range from -10 to 10 ° C, and in the case of the Swern oxidation reaction from -78 to 30 ° C.

The reaction time, in turn, depends on the method of carrying out the oxidation reaction, however, the reaction is preferably carried out over a period of 30 minutes to 12 hours, more preferably less than 2 hours.

[Step H] Preparation of a compound of formula (IB-3)

A compound of formula (I-B-3) can be prepared from a compound of formula (I-B-2) via a double bond migration reaction using a base.

In this reaction, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, benzene and toluene can be used as a solvent. Methanol and tetrahydrofuran are particularly preferred.

Sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium hydride, sodium hydride, potassium hydride, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, sodium methoxide, sodium ethoxide and tert can be used as a base in the α-hydrogen removal of the ketone group. potassium butoxide. Among them, sodium hydroxide, potassium hydroxide and potassium tert-butoxide are particularly preferred. The amount of base is usually from 1.0 to 4.0 equivalents with respect to the amount of the compound of formula (I-B-2), preferably from 1.0 to 1.5 equivalents.

The reaction temperature depends on the type of base and the solvent used, but usually the reaction is carried out at a temperature of from -10 to 120 ° C, more preferably from 10 to 50 ° C.

The reaction time depends on the reaction temperature and the type of base and solvent used, however, it usually ranges from 30 minutes to 4 hours, preferably it is less than 1 hour.

I-4. The synthesis of a compound of formula (II-A) from testosterone (I-C) of formula (I), where A is an oxo group (= O), B is a hydroxyl group (-OH), n is 0, and Δ ^{4 is} present :

According to Scheme 4, a compound of formula (I-C) is reacted with 1,2-ethanediol in the presence of an acid catalyst to give a compound of formula (I-C-1). This compound is subjected to a Wittig reaction with ethyltriphenylphosphonium halide in the presence of a strong base to give a compound of formula (I-C-3). Then, a compound of formula (I-A-3) is obtained by deprotecting the ketone group of a compound of formula (I-C-3), oxidized with selenium dioxide to introduce an alcohol group at position C-16, and a compound of formula (II-A is obtained ), guggulsterol.

Scheme 4

[Step I] Preparation of a compound of formula (IC-1)

To obtain a compound of formula (I-C-1), a compound of formula (I-C) is reacted with 1,2-ethanediol in the presence of an acid catalyst in a solvent.

As a solvent, chloroform, dichloromethane, tetrachloroethane, tetrahydrofuran, acetonitrile, benzene and toluene can be used. Among them, dichloromethane and benzene are particularly preferred.

As alkanediols, 1,2-ethanediol (ethylene glycol) and 1,3-propanediol can be used. Particularly preferred is 1,2-ethanediol.

Acid catalysts used in this reaction include boron trifluoroetherate (BF ₃ · Et ₂ O), zinc iodide, oxalic acid and p-toluenesulfonic acid. Among these compounds, p-toluenesulfonic acid is particularly preferred. The amount of acid used is typically from 0.01 to 2.0 equivalents with respect to the amount of alkanediol, preferably from 0.01 to 0.05 equivalents.

The reaction temperature depends on the type of solvent used, however, the reaction is usually carried out at a temperature of from -10 to 110 ° C, more preferably from 70 to 100 ° C. The reaction time depends on the reaction temperature and the type of solvent used, however, it usually ranges from 30 minutes to 12 hours, preferably less than 3 hours.

[Step J] Preparation of a compound of formula (IC-2)

A compound of formula (I-C-2) is obtained by reacting a compound of formula (I-C-1) with chromium oxide.

In this method, pyridinium chlorochromate (PCC) and pyridinium dichromate (PDC) can be used to oxidize the secondary alcohol group at position C-17 to the ketone group. Pyridinium chlorochromate is preferred.

The solvent used depends on the type of oxidizing agent. Preferably, dichloromethane is used with pyridinium chlorochromate (PCC), N, N-dimethylacetamide with pyridinium dichromate (PDC).

The amount of oxidizing reagent depends on its type, however, as a rule, it is from 1.0 to 5.0 equivalents with respect to the amount of the compound of formula (I-C-1), preferably from 1.5 to 2.0 equivalents.

The reaction temperature depends on the type of oxidizing reagent, but usually it is in the range from -10 to 30 ° C. The reaction time, in turn, depends on the type of oxidizing reagent, however, the reaction is preferably carried out over a period of 30 minutes to 12 hours, more preferably less than 2 hours.

[Step K] Preparation of a compound of formula (IC-3)

To obtain a compound of formula (I-C-3), preferably a compound of formula (I-C-2) is reacted with ethyltriphenylphosphonium halide (Ph ₃ P ⁺ CH ₂ CH ₃ X ^- ) in a non-aqueous solvent in the presence of a strong base.

Non-aqueous solvents suitable for this reaction include diethyl ether, tetrahydrofuran, hexane, heptane, methanol, ethanol, dimethyl sulfoxide, benzene, toluene, xylene and dimethyl sulfoxide. These solvents can be used individually or as a mixture of two or more solvents. Among these compounds, tetrahydrofuran and dimethyl sulfoxide are particularly preferred.

Ethyl triphenylphosphonium halides suitable for the Wittig reaction include ethyl triphenylphosphonium chloride (Ph ₃ P ⁺ CH ₂ CH ₃ Cl ^- ), ethyl triphenylphosphonium bromide (Ph ₃ P ⁺ CH ₂ CH ₃ Br ^- ) or ethyl triphenylphosphonium iodide (Ph ₃ P ⁺ CH ₂ CH ₃ I ^- ). Among these compounds, ethyltriphenylphosphonium bromide and ethyltriphenylphosphonium iodide are particularly preferred.

Strong bases suitable for the Wittig reaction include lithium hydride, sodium hydride, potassium hydride, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, sodium methoxide, sodium ethoxide or potassium tert-butoxide. Among these compounds, sodium hydride and potassium tert-butoxide are particularly preferred.

The amount of base used to prepare the ylide is typically from 1.0 to 4.0 equivalents with respect to ethyltriphenylphosphonium halide, preferably from 1.0 to 1.5 equivalents with respect to ethyltriphenylphosphonium halide.

The reaction temperature varies depending on the type of solvent used, however, usually it is in the range from -10 to 120 ° C. If the ethyltriphenylphosphonium halide reacts in the presence of a strong base in an anhydrous solvent with the formation of ylide, the reaction is carried out at a temperature of from -10 to 20 ° C, if the compound of formula (I-C-2) is subjected to the Wittig reaction, the reaction is carried out at a temperature in the range from - 25 to 100 ° C. Preferably, the reaction is carried out at a temperature of from 50 to 70 ° C, if the solvent is tetrahydrofuran, and at a temperature of from 20 to 80 ° C, if the solvent is dimethyl sulfoxide.

The reaction time, in turn, depends on the reaction temperature and the type of solvent used, however, the reaction is preferably carried out over a period of from 30 minutes to 1 day, more preferably less than 2 hours.

[Step L] Preparation of a compound of formula (IA-3)

The compound of formula (I-A-3) can be obtained by deprotecting the ketone group at the C-3 position of the compound of formula (I-C-3).

Solvents suitable for the deprotection reaction include distilled water, acetone, chloroform, dichloromethane, acetonitrile, tetrahydrofuran and glacial acetic acid. These solvents can be used individually or as a mixture of two or more solvents. Among these compounds, distilled water and acetone are particularly preferred.

Reagents such as pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid (TsOH), hydrochloric acid and glacial acetic acid can be used to remove the protective group. Pyridinium p-toluenesulfonate (PPTS) is particularly preferred.

The amount of reagent depends on the type of reagent used, but usually 0.05 to 0.5 equivalents are used with respect to the amount of the compound of formula (I-C-3), preferably 0.1 to 0.3 equivalents.

The reaction temperature depends on the type of solvent and reagent used, however, it usually ranges from 0 to 100 ° C, preferably from 30 to 60 ° C. The reaction time, in turn, depends on the reaction temperature and the type of reagent used, however, as a rule, it is in the range from 30 minutes to 1 day, preferably it is less than 3 hours.

I-5. The synthesis of the compounds of formula (II-B) from 16α, 17α-epoxypregnenolone (ID) of formula (I), where A is a hydroxyl group (-OH), B is a methyl ketone group (-C (O) CH ₃ ), n is 0, and Δ ^{5 is} present

According to Scheme 5, a compound of formula (ID) is reacted with hydrazine (NH ₂ NH ₂ ) in the presence of a base at high temperature to give a compound of formula (II-B), where C is a hydroxyl group (—OH) and Δ ^{5 is} present .

Scheme 5

[Step M] Preparation of a compound of formula (II-B)

In this method, hydrazine monohydrate (NH ₂ NH ₂ ) and hydrazine anhydride (NH ₂ NH ₂ ) can be used. Among them, hydrazine monohydrate with a purity of 95-98% is preferred. The amount of hydrazine is from 1.0 to 40 equivalents with respect to the amount of the compound of formula (ID), preferably from 1.5 to 2.5 equivalents with respect to the organometallic reagent used as the base, and from 10 to 20 equivalents with respect to alkali metal hydroxide used as a base.

Suitable solvents for this reaction include methanol, ethanol, butanol, ethyl ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, benzene, toluene, xylene, diethylene glycol dimethyl ether, diethylene glycol monomethyl ether and diethylene glycol. Among these compounds, tetrahydrofuran and diethylene glycol are particularly preferred.

As the base, sodium hydroxide, potassium hydroxide, lithium hydroxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, potassium diisopropylamide, sodium methoxide, sodium ethoxide and potassium tert-butoxide can be used. Among them, sodium hydroxide, potassium hydroxide and potassium diisopropylamide are particularly preferred. The amount of base depends on its type, but preferably it is from 2.0 to 15 equivalents in the case of using alkali metal hydroxide, from 1.0 to 3.0 equivalents in the case of using alkali metal hydride, from 1.0 to 3.0 equivalents in the case of using an organometallic reagent, from 1.0 to 4.0 equivalents in the case of using an alkali metal alcoholate.

The reaction temperature depends on the type of solvent and the base used, however, it usually ranges from -100 to 190 ° C, more preferably from -100 to -78 ° C in the case of alkali metal hydride and organometallic reagent, from 20 to 100 ° C in the case use of alkali metal alcoholate, from 80 to 160 ° C in case of using alkali metal hydroxide. The reaction time, in turn, depends on the reaction temperature and the type of base used, however, usually the reaction is carried out over a period of 30 minutes to 48 hours, preferably less than 4 hours.

I-6. The synthesis of a compound of formula (II-A) from progesterone of formula (I-E), where A is an oxo group (= O), B is a methyl ketone group (-C (O) CH ₃ ), n is 0, and Δ ^{4 is} present

In accordance with scheme 6, the ketone groups at positions C-3 and C-20 of the compounds of formula (IE) are reduced to alcohol groups to obtain a compound of formula (IE-1), and then this compound is reacted with a selective oxidizing agent to oxidize the alcohol group in position C-3 in the ketone group to obtain the compounds of formula (IE-2). After preparing a compound of formula (IE-3) by introducing a p-toluenesulfonyl group or methanesulfonyl group as a leaving group into an alcohol group at position C-20, it is reacted with a base to obtain a compound of formula (IE-4), which is a mixture E and Z isomers. The mixture is reacted with selenium dioxide to obtain guggulsterol, a compound of formula (II-A), by introducing an alcohol group at position C-16.

Scheme 6

[Step N] Preparation of a compound of formula (I-E-1)

A compound of formula (I-E-1) is obtained by reacting a compound of formula (I-E) with a reducing reagent.

Suitable solvents for this reaction include methanol, ethanol, diethyl ether, tetrahydrofuran and dichloromethane. Among these compounds, methanol and ethanol are particularly preferred.

For ketone reduction, lithium aluminum hydride (LAH), diisobutylaluminum hydride (DIBAL-H), sodium borohydride (NaBH ₄ ), lithium borohydride (LiBH ₄ ) and platinum catalyst can be used as a reducing agent in the hydride reduction reaction. Among these compounds, borohydride reducing reagents are preferred, and sodium borohydride (NaBH ₄ ) is particularly preferred. The amount of reducing agent is usually from 0.5 to 4.0 equivalents with respect to the amount of the compound of formula (IE), preferably from 1.5 to 2.5 equivalents.

The reaction temperature depends on the type of solvent and reducing agent used, however, it usually ranges from -100 to 60 ° C, preferably from -78 to 25 ° C. The reaction time depends on the reaction temperature and the type of solvent used, but usually the reaction is carried out over time, comprising from 30 minutes to 6 hours, preferably less than 2 hours.

[Step O] Preparation of a compound of formula (I-E-2)

A compound of formula (I-E-2) can be prepared by reacting a compound of formula (I-E-1) with a selective oxidizing agent.

For the selective oxidation of the alcohol group in this method, activated manganese dioxide (MnO ₂ ) can be used. The amount of oxidizing reagent is typically from 1.0 to 40 equivalents relative to the amount of the compound of formula (IE-1), preferably from 10 to 20 equivalents.

Suitable solvents in this reaction include pentane, hexane, heptane, petroleum ether, benzene, toluene, xylene, acetone, chloroform, dichloromethane and carbon tetrachloride. Among these compounds, dichloromethane is particularly preferred.

The reaction temperature depends on the type of solvent used, however, it usually ranges from -10 to 100 ° C, preferably from 20 to 50 ° C. The reaction time depends on the reaction temperature and the type of solvent used, however, the reaction is usually carried out over a period of 30 minutes to 12 hours, preferably less than 2 hours.

[Step P] Preparation of a compound of formula (I-E-3)

A compound of formula (I-E-3) can be prepared by reacting a compound of formula (I-E-2) with p-toluenesulfonyl chloride or methanesulfonyl chloride in the presence of a base.

In this reaction, p-toluenesulfonyl chloride or methanesulfonyl chloride can be used. The amount of reagent is usually from 1.0 to 4.0 equivalents with respect to the amount of the compound of formula (I-E-2), preferably from 2.0 to 3.0 equivalents.

Suitable solvents for this reaction include N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, tetrachloroethane, chloroform, dichloromethane, benzene, toluene or pyridine. Among these compounds, dichloromethane and pyridine are preferred.

As the base, pyridine, triethylamine, imidazole and N, N-dimethylaminopyridine can be used. Among these compounds, pyridine and N, N-dimethylaminopyridine are preferred. The amount of base is usually from 1.0 to 4.0 equivalents with respect to the amount of the compound of formula (I-E-2), preferably from 1.5 to 2.5 equivalents.

The reaction temperature depends on the type of solvent used, however, it usually ranges from -10 to 40 ° C, preferably from 0 to 25 ° C. The reaction time depends on the reaction temperature and the type of solvent used, however, usually the reaction is carried out over a period of from 1 hour to 1 day, more preferably less than 5 hours.

[Step Q] Preparation of a compound of formula (IE-4)

A compound of formula (I-E-4) can be prepared by reacting a compound of formula (I-E-3) with a strong base.

As the base in this reaction, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene and the amine salt of 1, 8-diazabicyclo [5.4.0] undec-7-ene. Among these compounds, sodium methoxide and pyridine are preferred. The amount of base is usually from 1.0 to 4.0 equivalents in the case of alkali metal hydride, alkali metal alcoholate and amine salt, respectively. Pyridine can be used both as a solvent and as a reagent.

Suitable solvents for this reaction include N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, butanol, tetrahydrofuran, tetrachloroethane, chloroform, dichloromethane, benzene, toluene and pyridine. Among these compounds, dimethyl sulfoxide, methanol and pyridine are preferred.

The reaction temperature depends on the type of solvent and base used, however, it usually ranges from -78 to 150 ° C, preferably from 25 to 120 ° C. The reaction time depends on the reaction temperature and the type of base used, however, usually the reaction is carried out over a period of from 1 hour to 1 day, more preferably less than 5 hours.

II. The synthesis of the compounds of formula (III)

II-1. Synthesis of a compound of formula (III), type E guggulsterone, from guggulsterol of formula (II-A)

According to Scheme 7, a compound of formula (III), type E guggulsterone, can be prepared by reacting a compound of formula (II-A) with an oxidizing agent.

Scheme 7

[Step R] Preparation of type E guggulsterone, a compound of formula (III)

Type E guggulsterone of formula (III) can be prepared by reacting a guggulsterol of formula (II-A) with an oxidizing agent.

Pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent and activated manganese dioxide can be used as an oxidizing reagent for the oxidation of a secondary alcohol group to a ketone group. Among these compounds, Jones reagent and activated manganese dioxide are preferred. Activated manganese dioxide is particularly preferred.

Suitable solvents for this reaction include pentane, hexane, heptane, petroleum ether, benzene, toluene, xylene, dimethyl sulfoxide, acetone, chloroform, dichloromethane, tetrachloroethane, diethyl ether and tetrahydrofuran. Among these compounds, dichloromethane is preferred. In this reaction, activated manganese dioxide can be used without solvent.

The amount of oxidizing reagent depends on its type, but usually it is from 1.0 to 20 equivalents relative to the amount of the compound of formula (II-A), preferably from 5.0 to 10 equivalents in the case of activated manganese dioxide.

The reaction temperature depends on the type of solvent used, however, it usually ranges from -10 to 100 ° C, preferably from 20 to 50 ° C. The reaction time depends on the reaction temperature and the type of solvent used, however, the reaction is usually carried out over a period of 30 minutes to 12 hours, more preferably less than 2 hours.

II-2. Synthesis of a compound of formula (III), type E guggulsterone, from a compound of formula (II-B)

According to Scheme 8, a compound of formula (III), type E guggulsterone, can be prepared by reacting a compound of formula (II-B) with an oxidizing agent.

Scheme 8

[Stage S] Obtaining guggulsterone type E of the formula (III)

Guggulsterone of formula (III) can be obtained using the Oppenauer oxidation reaction by reacting a compound of formula (II-B) with an aluminum oxidizing reagent.

As aluminum oxidizing reagent in the oxidation reaction of Oppenauer, aluminum isopropoxide (Al [OCH (CH ₃ ) ₂ ] ₃ ), tri-sec-butoxide aluminum (Al [OCH (CH ₃ ) CH ₂ CH ₃ ] ₃ ), tri- aluminum tert-butoxide (Al [OC (CH ₃ ) ₃ ] ₃ ) and aluminum phenoxide (Al [OC ₆ H ₅ ] ₃ ). Among these compounds, aluminum isopropoxide is preferred. The amount of aluminum oxidizing reagent is typically from 0.3 to 1.5 equivalents with respect to the compound of formula (II-B), preferably from 0.5 to 1.0 equivalent.

Suitable non-aqueous solvents for this reaction include benzene, toluene, xylene and mesitylene. Among these compounds, benzene and toluene are preferred.

As reducing agents in the Oppenauer oxidation reaction, acetone, ethyl methyl ketone, acetophenone, benzophenone and cyclohexanone can be used. Among these compounds, ethyl methyl ketone and cyclohexanone are preferred.

The reaction temperature depends on the type of solvent used, however, it usually ranges from 50 to 180 ° C. The reaction temperature affects the regioselectivity of the final product, guggulsterone. Type E guggulsterone is obtained only if the reaction is carried out at a temperature of from 50 to 100 ° C, while a mixture of E- and Z-guggulsterones is obtained if the reaction is carried out at a temperature of from 120 to 180 ° C.

The reaction time depends on the reaction temperature and the type of solvent used, however, usually the reaction is carried out over a period of 30 minutes to 4 hours, more preferably less than 2 hours.

III. The synthesis of the compounds of formula (IV)

Synthesis of a compound of formula (IV), type Z guggulsterone, from a compound of formula (III), type E guggulsterone

In accordance with Scheme 9, type Z guggulsterone of formula (IV) can be prepared using a photochemical reaction, a thermochemical reaction or an acid catalyst of type E guggulsterone of formula (III).

Scheme 9

[Method T] Obtaining Z-guggulsterone of formula (IV)

Methylene blue, methylene green and Bengal pink can be used as a photosensitizer in the photochemical reaction involving type E guggulsterone. The amount of photosensitizer is usually from 0.01 to 0.2 equivalents with respect to the compound of formula (III), preferably from 0.05 to 0.1 equivalents.

As a light source, as a rule, you can use a tungsten lamp with a power of 60 to 500 watts, however, it is preferable to use a tungsten lamp with a power of 150 to 300 watts.

Solvents suitable for the photochemical reaction include distilled water, methanol, ethanol, acetonitrile, acetone, tetrachloroethane, chloroform, dichloromethane, tetrahydrofuran, benzene, toluene and xylene. These solvents can be used individually or as a mixture of two or more solvents. Among these compounds, dichloromethane, chloroform, acetonitrile, methanol and ethanol are particularly preferred. Chloroform and methanol are particularly preferred.

The reaction temperature depends on the type of solvent used, however, it usually ranges from -10 to 100 ° C, preferably from 20 to 50 ° C.

The reaction time depends on the strength of the light source, the reaction temperature and the type of photosensitizer used, however, usually the reaction is carried out for a period of time from 1 hour to 48 hours, more preferably less than 10 hours.

Solvents suitable for the thermochemical reaction include benzene, toluene, xylene and mesitylene. Among these compounds, toluene is preferred.

The reaction temperature depends on the type of solvent used, however, it usually ranges from 80 to 200 ° C, preferably from 100 to 130 ° C.

The reaction time depends on the reaction temperature and the type of solvent used, however, the reaction is usually carried out over a period of 1 to 48 hours, more preferably less than 2 hours.

As the acid catalyst in the reaction using the acid catalyst, p-toluenesulfonic acid and dilute hydrochloric acid (0.1-3.0 N HCl) can be used. The amount of acid catalyst is from 0.01 to 0.5 equivalents with respect to the amount of the compound of formula (III), preferably from 0.05 to 0.2 equivalents.

Solvents suitable for the reaction using an acid catalyst include acetonitrile, acetone, tetrachloroethane, chloroform, dichloromethane, tetrahydrofuran, benzene, toluene and xylene. These solvents can be used individually or as a mixture of two or more solvents. Among these compounds, dichloromethane, chloroform, acetonitrile, benzene and toluene are particularly preferred. More preferably, chloroform and benzene are used for p-toluenesulfonic acid, and acetonitrile, respectively, is used for dilute hydrochloric acid.

The reaction temperature depends on the type of solvent used, however, it usually ranges from -10 to 160 ° C, preferably from 30 to 80 ° C.

The reaction time depends on the reaction temperature and the type of acid catalyst used, however, as a rule, the reaction is preferably carried out over a period of 30 minutes to 10 hours, more preferably less than 1 hour.

Type E guggulsterone, a compound of formula (III), and type Z guggulsterone, a compound of formula (VI), are known as drugs for treating hyperlipidemia in humans.

EXAMPLES

The present invention is more specifically illustrated by the following examples. However, it should be understood that these examples in no way limit the present invention.

Example 1. Synthesis of cyclo-3- (1,2-ethanediyl dithioacetal) -4-androsten-17-one of formula (I-A-1) from a compound of formula (I-A) [Step A]

4-Androsten-3,17-dione (IA) (28.6 g, 100 mmol) was completely dissolved in glacial acetic acid (100 ml) at 25 ° C, and 1,2-ethanedithiol (10.4 ml, 110 mmol) and p-toluenesulfonic acid (8.6 g, 50 mmol). The reaction mixture was allowed to react at room temperature, after which it was poured into distilled water (100 ml) and thoroughly stirred at room temperature for 15 minutes. The resulting mixture was extracted with ethyl acetate (3 × 50 ml), the organic layer was washed with brine and distilled water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by column chromatography, eluting with ethyl acetate / hexane (2/8), and the title compound was obtained (27.2 g, 75% yield).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.51 (s, 1H), 3.37 (m, 3H), 3.23 (m, 1H), 2.39 (q, 1H), 2, 17-0.84 (the bulk of the steroid molecule and 1.04 (s, 3H), 0.88 (s, 3H) = 24H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 221.3, 146.1, 125.0, 66.2, 54.6, 51.4, 48.0, 40.4, 40.0, 38.4, 37.7, 37.1, 36.2, 35.7, 32.2, 31.9, 31.8, 22.2, 21.0, 18.9, 14.1.

Example 2. Synthesis of cyclo-3- (1,2-ethanediyl dithioacetal) -4-androsten-17-one of formula (I-A-1) from a compound of formula (I-A) [Step A]

4-Androsten-3,17-dione (IA) (28.6 g, 100 mmol) was completely dissolved in absolute methanol (150 ml) at 0 ° C and 1,2-ethanedithiol (15 ml, 179 mmol) was added to the resulting solution. ), and then slowly add an acid catalyst, BF ₃ · ether (14 ml). The reaction mixture was allowed to react at 20 ° C for 10 hours. After completion of the reaction, the resulting mixture was evaporated under reduced pressure to remove methanol, and treated with dichloromethane (100 ml) and 5% NaHCO ₃ solution. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (33.4 g, yield 92%).

Example 3. Synthesis of cyclo-3- (1,2-ethanediyl dithioacetal) -4.17 (20) -cis-androstene of formula (I-A-2) from a compound of formula (I-A-1) [Step B]

Ethyltriphenylphosphonium bromide (44.6 g, 120 mmol) was dissolved in dry tetrahydrofuran (200 ml) at 0 ° C, 120 ml (120 mmol). Potassium tert-butoxide in anhydrous tetrahydrofuran (1 M solution) was slowly added to the resulting solution over 15 minutes. After complete addition, the reaction mixture was allowed to react for another 30 minutes at room temperature, and then the compound of formula (IA-1) (33.4 g, 92.1 mmol) in tetrahydrofuran (150 ml) was slowly added at room temperature. The reaction mixture was stirred at room temperature for another 2 hours. The resulting mixture was evaporated under reduced pressure and 250 ml of a solvent mixture of hexane / ethyl ether (v / v = 10/1) was added to precipitate a by-product, triphenylphosphine oxide (Ph ₃ P = O), which was then filtered off. The organic layer was washed with brine and distilled water, dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (33.1 g, 96% yield).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.51 (s, 1H), 5.11 (m, 1H), 3.40 (m, 3H), 3.25 (m, 1H), 2, 21-0.77 (the bulk of the steroid molecule and 1.05 (s, 3H), 0.91 (s, 3H) = 28H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 150.5, 146.9, 124.5, 113.8, 66.3, 56.2, 54.5, 44.6, 40.4, 40.0, 38.5, 37.7, 37.4, 37.1, 35.7, 33.0, 32.5, 31.8, 24.8, 21.8, 18.9, 17, 2, 13.5.

Example 4. Synthesis of cyclo-3- (1,2-ethanediyl dithioacetal) -4.17 (20) -cis-androstene of formula (I-A-2) from a compound of formula (I-A-1) [Step B]

Ethyl triphenylphosphonium bromide (37.1 g, 100 mmol) was dissolved in anhydrous dimethyl sulfoxide (150 ml) at 15 ° C and sodium hydride (2.5 g, 105 mmol) was slowly added. After complete addition, the reaction mixture was stirred for 30 minutes at room temperature, and then the compound of formula (IA-1) (30 g, 82.7 mmol) was slowly added at room temperature. The reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction, brine (200 ml) and ethyl acetate (200 ml) were poured into the reaction mixture, and the organic layer was separated. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. A mixture of hexane and ethyl ether (v / v = 10/1) (250 ml) was added to the resulting residue to precipitate a by-product, triphenylphosphine oxide (Ph ₃ P = O), which was then filtered off. The solvent was evaporated under reduced pressure to obtain the title compound (28.2 g, yield 91%).

Example 5. Synthesis of 4.17 (20) -cis-pregnadiene-3-one of formula (I-A-3) from a compound of formula (I-A-2) [Step C]

The compound of formula (IA-2) (33 g, 88 mmol) was dissolved in glacial acetic acid (200 ml) at room temperature, and selenium dioxide (4.8 g, 44 mmol) was immediately added to the resulting mixture. The resulting reaction mixture was stirred for 2 hours at room temperature, after which distilled water (300 ml) was added. The reaction mixture was extracted with ethyl acetate (200 ml) three times and the combined organic layer was washed with 10% aqueous NaHCO ₃ solution. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was subjected to silica chromatography, eluting with ethyl acetate / hexane (v / v = 3/7), and the title compound was obtained (21.8 g, 83% yield).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.74 (s, 1H), 5.14 (q, 1H), 2.44-0.8 (bulk of the steroid molecule and 1.71 (d, 3H) ), 1.23 (s, 3H), 0.93 (s, 3H) = 28H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 199.9, 171.7, 150.0, 124.21, 114.1, 56.0, 54.2, 44.5, 39.0, 37.2, 36.1, 35.5, 34.4, 33.3, 32.3, 31.7, 24.8, 21.6, 17.7, 17.2, 13.5.

Example 6. Synthesis of 4.17 (20) -cis-pregnadien-3-one of the formula (I-A-3) from the compound of the formula (I-A-2) [Step C]

Silver nitrate (4.7 g, 30 mmol) and iodide (3.8 g, 15 mmol) of silver are added to a 5% solution of tetrahydrofuran in distilled water (200 ml) at room temperature, after which it is stirred for 1 hour. To the resulting reaction mixture at room temperature, a compound of formula (I-A-2) (30 g, 80 mmol) is slowly added and then stirred for 3 hours at room temperature. At 0 ° C, a saturated aqueous sodium thiosulfide solution was added and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by column chromatography, eluting with ethyl acetate / hexane (v / v 3/7), and the title compound was obtained (21 g, 88% yield).

Example 7. Synthesis of E-guggulsterol [4.17 (20) -E-pregnadiene-3-one-16α-ol] of the formula (II-A) from the compound of the formula (I-A-3) [Step D]

With vigorous stirring of selenium dioxide (1.9 g, 18 mmol) in dichloromethane (100 ml) at room temperature, tert-butyl peroxide (18 ml) was slowly added to the mixture and then stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C and a compound of formula (I-A-3) (21 g, 70 mmol) in dichloromethane (100 ml) was added over 10 minutes. The mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the solvent was removed by evaporation under reduced pressure and extracted with ethyl acetate and distilled water. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (20 g, yield 91%).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.75 (s, 1H), 5.61 (m, 1H), 4.46 (s, 1H), 2.44-0.94 (main part of the molecule steroid and 1.75 (d, 3H), 1.22 (s, 3H), 0.94 (s, 3H) = 27H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 199.8, 171.4, 155.25, 124.3, 120.3, 74.6, 54.1, 52.3, 44.6, 39.0, 37.4, 36.0, 35.4, 34.9, 34.3, 33.2, 21.5, 17.8, 17.7, 13.6.

Example 8. Synthesis of E-guggulsterol [4.17 (20) -E-pregnadiene-3-one-16α-ol] of the formula (II-A) from the compound of the formula (I-A-3) [Step D]

While stirring selenium dioxide (3.9 g, 35 mmol) in dichloromethane (100 ml), tert-butyl peroxide (18 ml) was added dropwise and then stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C and the compound of formula (I-A-3) (21 g, 70 mmol) in dichloromethane (100 ml) was slowly added over 10 minutes. The reaction mixture was warmed to room temperature, then stirred for 1 hour. After completion of the reaction, the solvent was removed by evaporation under reduced pressure and extracted with ethyl acetate and distilled water. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (21 g, 93% yield).

Example 9. Synthesis of E-guggulsterol [4.17 (20) -E-pregnadiene-3-one-16α-ol] of the formula (II-A) from the compound of the formula (I-A-3) [Step D]

While stirring selenium dioxide (2 g, 18 mmol) in dioxane (150 ml) at 0 ° C, N-methylmorpholine-N-oxide (6 g, 50 mmol) was slowly added and then stirred for 1 hour. A compound of formula (I-A-3) (9 g, 35 mmol) was slowly added, the reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was evaporated to dryness under reduced pressure, and the resulting mixture was dissolved in ethyl acetate (100 ml). The resulting mixture was washed with brine and distilled water. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by column chromatography, eluting with ethyl acetate / hexane (v / v = 1/1), and the title compound was obtained (22 g, 82% yield).

Example 10. Synthesis of 5.17 (20) -cis-pregnadiene-3β-ol of formula (IB-1) from a compound of formula (IB) [Step E]

Ethyl triphenylphosphonium bromide (130 g, 350 mmol) was dissolved in dry dimethyl sulfoxide (400 ml) at 15 ° C and sodium hydride (8.6 g, 360 mmol) was slowly added. After confirming completion of the addition, the reaction mixture was stirred for another 1 hour, and at room temperature DHEA of formula (IB) (28.8 g, 100 mmol) was added to the reaction mixture. The reaction mixture was slowly heated to 80 ° C and stirred for another 2 hours. After completion of the reaction, the reaction mixture was extracted three times with brine (800 ml) and ethyl acetate (300 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. A mixture of hexane and ethyl ether (v / v = 10/1) (400 ml) was added to the resulting residue to precipitate a by-product, triphenylphosphine oxide (Ph ₃ P = O), which was then filtered off. The filtrate was evaporated under reduced pressure to obtain the title compound (28.6 g, 95% yield).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.38 (d, 1H), 5.16 (m, 1H), 3.53 (m, 1H), 2.42-0.92 (bulk of the molecule steroid and 1.70 (d, 3H), 1.04 (s, 3H), 0.92 (s, 3H) = 29H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 150.6, 141.2, 122.0, 113.9, 72.1, 56.9, 50.6, 44.4, 42.7, 37.6, 37.4, 37.0, 32.1, 32.0, 31.9, 31.8, 24.9, 21.6, 19.8, 17.0, 13.5.

Example 11. Synthesis of 5.17 (20) -cis-pregnadiene-3β-ol of the formula (IB-1) from the compound of the formula (IB) [Step E]

Ethyl triphenylphosphonium bromide (92.8 g, 250 mmol) was dissolved in dry dimethyl sulfoxide (300 ml) at 15 ° C and sodium hydride (6.3 g, 260 mmol) was added slowly, the reaction mixture was stirred for another 1 hour at room temperature and slowly added DHEA of formula (I-B) (28.8 g, 100 mmol). The reaction mixture was slowly heated to 80 ° C and stirred for another 2 hours. After completion of the reaction, the reaction mixture was extracted three times with brine (600 ml) and ethyl acetate (200 ml). The combined organic layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. A mixture of hexane and ethyl ether (v / v = 10/1) (300 ml) was added to the residue to precipitate a by-product, triphenylphosphine oxide (Ph ₃ P = O), which was then filtered off. The filtrate was evaporated to dryness under reduced pressure. The residue was subjected to silica chromatography, eluting with ethyl acetate / hexane (v / v = 3/7), and the title compound was obtained (25.5 g, 85% yield).

Example 12. Synthesis of 5.17 (20) -cis-pregnadiene-3β-ol of formula (IB-1) from a compound of formula (IB) [Step E]

Ethyl triphenylphosphonium bromide (92.8 g, 250 mmol) was stirred in dry tetrahydrofuran (300 ml) at 15 ° C and potassium tert-butoxide in dry tetrahydrofuran (1 mol.) (280 ml, 280 mmol) was added slowly over 15 minutes. ) After complete addition, the reaction mixture was stirred for another 1 hour at room temperature, and DHEA of formula (IB) (18.2 g, 63 mmol) was slowly added. The reaction mixture was heated to reflux for 6 hours. After completion of the reaction, the solvent was removed under reduced pressure, a mixture of hexane and ethyl ether (v / v = 10/1) (300 ml) was added to precipitate a by-product, triphenylphosphine oxide (Ph ₃ P = O), which was then filtered off. The filtrate was evaporated to dryness under reduced pressure. The resulting residue was subjected to silica chromatography, eluting with ethyl acetate / hexane (v / v = 3/7), and the title compound was obtained (15.7 g, 83% yield).

Example 13. Synthesis of 5.17 (20) -E-pregnadiene-3β, 16α-diol of the formula (II-B) from the compound of the formula (I-B-1) [Step F]

With vigorous stirring of selenium dioxide (5.3 g, 476 mmol) in dichloromethane (200 ml) at 25 ° C, tert-butyl peroxide (36 ml) was slowly added to the mixture. After 30 minutes, the reaction mixture was cooled to 0 ° C and a compound of formula (IB-1) (28.6 g, 95.2 mmol) in dichloromethane (100 ml) was added over 10 minutes, followed by stirring for another 3.5 hours. After completion of the reaction, the combined organic layer was washed with brine and distilled water, dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (27.4 g, 91% yield).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.60 (q, 1H), 5.38 (s, 1H), 4.46 (s, 1H), 3.55 (m, 1H), 2, 30-0.91 (the main part of the steroid molecule and 1.86 (d, 3H), 1.05 (s, 3H), 0.91 (s, 3H) = 28H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 155.8, 141.2, 121.9, 120.0, 74.8, 72.1, 53.2, 50.6, 44.6, 42.7, 37.7, 37.6, 37.0, 35.6, 32.0, 31.2, 21.5, 19.7, 17.7, 13.6.

Example 14. Synthesis of 5.17 (20) -E-pregnadiene-3β, 16α-diol of the formula (II-B) from the compound of the formula (I-B-1) [Step F]

While stirring selenium dioxide (9.2 g, 83.2 mmol) in dichloromethane (250 ml) at 25 ° C, tert-butyl peroxide (36 ml) was slowly added to the mixture. After 30 minutes, the reaction mixture was cooled to 0 ° C and a compound of formula (IB-1) (25 g, 83.2 mmol) in dichloromethane (100 ml) was slowly added over 10 minutes. The reaction mixture was stirred at the same temperature for another 2 hours. After completion of the reaction, the organic layer was washed with brine and distilled water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (25.8 g, yield 98%).

Example 15. Synthesis of 5.17 (20) -cis-pregnadien-3-one of the formula (I-B-2) from the compound of the formula (I-B-1) [Step G]

The compound of formula (IB-1, 25 g, 83 mmol) is dissolved in dichloromethane (250 ml) at 0 ° C and then 4Å molecular sieves (3 g) and pyridinium chlorochromate (PCC, 21.5 g, 100 mmol) are added. . The reaction mixture was stirred at the same temperature for 2 hours, after which the reaction was stopped by the addition of ethyl ether (250 ml). The resulting mixture was purified in advance by removing the by-product by passing the mixture through a flash column of silica, followed by evaporation of the filtrate to dryness. The residue was subjected to silica chromatography, eluting with ethyl acetate / hexane (v / v = 3/7), and the title compound was obtained (22.5 g, yield 91%).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.38 (t, 1H), 5.17 (m, 1H), 3.28 (d, 1H), 2.85 (q, 1H), 2, 82-0.80 (the bulk of the steroid molecule and 1.70 (d, 3H), 1.22 (s, 3H), 0.94 (s, 3H) = 26H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 210.6, 150.3, 139.0, 123.2, 114.0, 56.8, 49.6, 48.7, 44.5, 38.0, 37.4, 37.3, 37.2, 32.0, 31.9, 31.8, 24.9, 21.9, 19.6, 17.1, 13.5.

Example 16. Synthesis of 5.17 (20) -cis-pregnadien-3-one of formula (I-B-2) from a compound of formula (I-B-1) [Step G]

The compound of formula (IB-1, 5.0 g, 17 mmol) is dissolved in acetone (100 ml) at 10 ° C. and then 8N is slowly added. Jones reagent (3 ml). The reaction mixture was kept at the same temperature for 30 minutes, after which the solvent was evaporated under reduced pressure. Then, the resulting mixture was extracted with ethyl acetate and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting mixture was purified by column chromatography (eluent: ethyl acetate / hexane solvent = 3/7) to obtain the title compound (3.8 g, yield 74%).

Example 17. Synthesis of 4.17 (20) -cis-pregnadiene-3-one of formula (I-B-3) from a compound of formula (I-B-2) [Step H]

The compound of formula (IB-2) (22 g, 73.7 mmol) is dissolved in methanol (100 ml) at room temperature, and then potassium hydroxide (5 g) is dissolved in the resulting solution. The reaction mixture was heated to reflux for 40 minutes, then cooled to room temperature. The solvent was removed by evaporation under reduced pressure, and the mixture was extracted with ethyl acetate and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (20 g, yield 91%).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.74 (s, 1H), 5.14 (q, 1H), 2.44-0.8 (bulk of the steroid molecule and 1.71 (d, 3H) ), 1.23 (s, 3H), 0.93 (s, 3H) = 28H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 199.9, 171.7, 150.0, 124.21, 114.1, 56.0, 54.2, 44.5, 39.0, 37.2, 36.1, 35.5, 34.4, 33.3, 32.3, 31.7, 24.8, 21.6, 17.7, 17.2, 13.5.

Example 18. Synthesis of 4.17 (20) -cis-pregnadien-3-one of formula (I-B-3) from a compound of formula (I-B-2) [Step H]

The compound of the formula (IB-2, 15 g, 50 mmol) is dissolved in dry tetrahydrofuran (80 ml) at 10 ° C, and then potassium tert-butoxide in dry tetrahydrofuran (1 M solution, 60 ml, 60 mmol). The reaction mixture was slowly warmed to room temperature, then stirred for another 1 hour. Then, the solvent was evaporated under reduced pressure to dryness, and the resulting mixture was extracted with ethyl acetate and brine. The resulting organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (14.2 g, 95% yield).

Example 19. Synthesis of cyclo-3- (1,2-ethanediylacetal) -5-androsten-17β-ol of formula (I-C-1) from a compound of formula (I-C) [Step I]

Testosterone (I-C, 28.8 g, 100 mmol) was dissolved in benzene (200 ml) at 25 ° C and 1,2-ethanediol (6.2 ml, 110 mmol) and p-toluenesulfonic acid were added to the resulting solution ( 0.2 g, 1 mmol). To remove moisture, the mixture is heated at the boiling temperature under reflux in a Dean-Stark apparatus for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and saturated NaHCO ₃ solution (100 ml) was added to separate the benzene layer, and the remaining aqueous layer was extracted with ethyl acetate (80 ml) three times. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 3/7) to obtain the title compound (25.3 g, yield 76%).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.35 (t, 1H), 3.97 (q, 4H), 3.66 (t, 1H), 2.56 (q, 1H), 2, 10-0.77 (the bulk of the steroid molecule and 1.06 (s, 3H), 0.78 (s, 3H) = 25H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 140.7, 122.2, 109.8, 82.2, 64.8, 64.6, 51.8, 50.3, 43.2, 42.2, 37.1, 37.0, 36.7, 32.4, 31.8, 31.5, 31.0, 23.8, 21.1, 19.3, 11.3.

Example 20. Synthesis of cyclo-3- (1,2-ethanediylacetal) -5-androsten-17β-ol of formula (I-C-1) from a compound of formula (I-C) [Step I]

Testosterone (I-C, 28.8 g, 100 mmol) was dissolved in benzene (200 ml) at 25 ° C and 1,2-ethanediol (18.6 ml, 330 mmol) and p-toluenesulfonic acid were added to the resulting solution ( 1 g, 5 mmol). To remove moisture, the mixture is heated at the boiling temperature under reflux in a Dean-Stark apparatus for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and saturated NaHCO ₃ solution (100 ml) was added to separate the benzene layer, and the remaining aqueous layer was extracted with ethyl acetate (80 ml) three times. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 3/7) to obtain the title compound (29 g, 87% yield).

Example 21. Synthesis of cyclo-3- (1,2-ethanediyl dithioacetal) -5-androsten-17-one of formula (I-C-2) from a compound of formula (I-C-1) [Step J]

The compound of formula (I-C-1, 28 g, 84 mmol) is dissolved in dichloromethane (250 ml) at 0 ° C, and then 4Å molecular sieves (3 g) and pyridinium chlorochromate (PCC, 21.5 g, 100 mmol) are added. ) The reaction mixture was stirred at the same temperature for 2 hours, after which the reaction was stopped by the addition of ethyl ether (200 ml). The reaction mixture was passed through a flash column to remove a by-product, then the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 3/7) to obtain the title compound (23 g, 83% yield).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.29 (s, 1H), 3.87 (s, 1H), 2.48 (d, 1H), 2.26 (q, 1H), 2, 04-0.98 (the main part of the steroid molecule and 0.98 (s, 3H), 0.81 (s, 3H) = 26H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 221.2, 140.7, 121.7, 109.6, 64.8, 64.6, 52.0, 50.1, 47.8, 42.1, 37.1, 36.6, 36.1, 31.8, 31.8, 31.3, 31.0, 30.1, 22.2, 20.7, 19.2, 13, 9.

Example 22. Synthesis of cyclo-3- (1,2-ethanediyl dithioacetal) -5-androsten-17-one of formula (I-C-2) from a compound of formula (I-C-1) [Step J]

The compound of formula (I-C-1, 28 g, 84 mmol) is dissolved in dichloromethane (300 ml) at 0 ° C, and then 4Å molecular sieves (5 g) and pyridinium chlorochromate (36 g, 168 mmol) are added. The reaction mixture was stirred at the same temperature for 2 hours, after which the reaction was stopped by the addition of ethyl ether (250 ml). The reaction mixture was treated with molecular sieves to remove a by-product, then the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 3/7) to obtain the title compound (24.4 g, 88% yield).

Example 23. Synthesis of cyclo-3- (1,2-ethanediylacetal) -5.17 (20) -cis-androsten of formula (I-C-3) from a compound of formula (I-C-2) [Step K]

Ethyltriphenylphosphonium bromide (37 g, 100 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml) at 0 ° C, and then potassium tert-butoxide in anhydrous tetrahydrofuran (1 M solution) (110 ml, 110 mmol) was slowly added over 15 minutes. After complete addition, the reaction mixture was allowed to react at room temperature for another 30 minutes and then the compound of formula (I-C-2) (24 g, 83.2 mmol) in tetrahydrofuran (150 ml) was slowly added at room temperature. The reaction mixture was heated at reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was poured into a mixture of hexane and ethyl ether (v / v = 10/1, 250 ml) to precipitate triphenyl phosphate oxide (Ph ₃ P = O), which was then filtered off. The organic layer was washed with brine and distilled water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/9) to obtain the title compound (23.1 g, 81% yield).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.38 (t, 1H), 5.16 (q, 1H), 3.97 (m, 4H), 2.57 (q, 1H), 2, 23-0.89 (the main part of the steroid molecule and 1.68 (d, 3H), 1.06 (s, 3H), 0.92 (s, 3H) = 27H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 150.6, 140.5, 122.5, 113.9, 109.9, 64.9, 64.6, 56.9, 50.1, 44.4, 42.2, 37.4, 37.1, 36.7, 31.8, 31.8, 31.5, 24.9, 21.6, 19.2, 17.0, 13, 5.

Example 24. Synthesis of cyclo-3- (1,2-ethanediylacetal) -5.17 (20) -cis-androsten of formula (I-C-3) from a compound of formula (I-C-2) [Step K]

Ethyl triphenylphosphonium bromide (40 g, 105 mmol) was dissolved in anhydrous tetrahydrofuran (250 ml) at 10 ° C, and then sodium hydride (2.6 g, 110 mmol) was slowly added. After complete addition, the reaction mixture was stirred at room temperature for another 30 minutes, and then the compound of formula (I-C-2) (24 g, 83.2 mmol) was slowly added at room temperature. The reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was washed with brine (200 ml) and ethyl acetate (200 ml), and the organic layer was separated. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was poured into a mixture of hexane and ethyl ether (v / v = 10/1, 250 ml) to precipitate triphenylphosphate oxide (Ph ₃ P = O), which was then filtered off. The filtrate was evaporated under reduced pressure to obtain the title compound (26.5 g, 93% yield).

Example 25. Synthesis of 4.17 (20) -cis-pregnadiene-3-one of formula (I-A-3) from a compound of formula (I-C-3) [Step L]

The compound of formula (I-C-3, 26 g, 76 mmol) is dissolved in acetone (200 ml) containing 5% distilled water, then p-toluenesulfonate pyridinium (PPTS, 1.8 g, 7 mmol) is added. The reaction mixture is heated at 40 ° C for 2 hours. After completion of the reaction, acetone was removed under reduced pressure, and the reaction mixture was extracted with distilled water (100 ml) and ethyl acetate (150 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (21.3 g, yield 94%).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.74 (s, 1H), 5.14 (q, 1H), 2.44-0.8 (m, 19H), 1.71 (d, 3H ), 1.23 (s, 3H), 0.93 (s, 3H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 199.9, 171.7, 150.0, 124.21, 114.1, 56.0, 54.2, 44.5, 39.0, 37.2, 36.1, 35.5, 34.4, 33.3, 32.3, 31.7, 24.8, 21.6, 17.7, 17.2, 13.5.

Example 26. Synthesis of 4.17 (20) -cis-pregnadiene-3-one of formula (I-A-3) from a compound of formula (I-C-3) [Step L]

The compound of formula (I-C-3, 5 g, 15 mmol) is mixed with 75% glacial acetic acid (45 ml) and then the mixture is heated at 60 ° C for 30 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with brine (30 ml) and ethyl acetate (50 ml × 3). The glacial acetic acid remaining in the organic layer was removed by adding a saturated aqueous solution of NaHCO ₃ and distilled water, the organic layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (eluent: ethyl acetate / hexane = 3/7) to obtain the title compound (3.8 g, 84% yield).

Example 27. Synthesis of 5.17 (20) -E-pregnadiene-3β, 16α-diol of the formula (II-B) from the compound of the formula (I-D) [Step M]

The compound of formula (I-D, 33.1 g, 100 mmol) and potassium hydroxide (50 g) are dissolved in diethylene glycol (200 ml) at room temperature, and then hydrazine monohydrate (purity 98%, 97 ml, 2 mol.) Is added. The reaction mixture was heated at 120 ° C. under reflux for 1 hour, then the refrigerator was removed and the reaction mixture was heated another 2 hours at 160 ° C. The completion of the reaction was confirmed by TLC, after which the reaction mixture was cooled to room temperature. The reaction mixture was mixed with distilled water (200 ml) and then extracted with chloroform (200 ml) three times. The organic layer was dried over magnesium sulfate, filtered and the solvent was removed by evaporation under reduced pressure to obtain the title compound (28.8 g, yield 91%).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.60 (q, 1H), 5.38 (s, 1H), 4.46 (s, 1H), 3.55 (m, 1H), 2, 30-0.91 (the main part of the steroid molecule and 1.86 (d, 3H), 1.05 (s, 3H), 0.91 (s, 3H) = 28H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 155.8, 141.2, 121.9, 120.0, 74.8, 72.1, 53.2, 50.6, 44.6, 42.7, 37.7, 37.6, 37.0, 35.6, 32.0, 32.0, 31.2, 21.5, 19.7, 17.7, 13.6.

Example 28. Synthesis of 4-pregnen-3,20-diol of the formula (I-E-1) from the compound of the formula (I-E) [Step N]

The compound of formula (IE, 31.5 g, 100 mmol) is dissolved in methanol (300 ml) at 0 ° C and then sodium borohydride (NaBH ₄ , 7.6 g, 200 mmol) is carefully added. The reaction proceeds at 20 ° C for 2 hours, after which the solvent is removed by evaporation under reduced pressure. The reaction mixture was extracted with ethyl acetate and brine, the organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (31.2 g, yield 98%).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.30 (s, 1H), 4.16 (s, 1H), 3.74 (d, 1H), 2.22-0.77 (bulk of the molecule steroid and 1.15 (d, 3H), 1.08 (s, 3H), 0.80 (s, 3H) = 29H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 148.0, 123.8, 70.9, 68.3, 59.0, 56.1, 54.9, 42.8, 40.4, 37.8, 36.3, 35.8, 33.6, 32.6, 29.9, 26.0, 24.9, 24.0, 21.3, 19.3, 12.8.

Example 29. Synthesis of 4-pregnen-3,20-diol of the formula (I-E-1) from the compound of the formula (I-E) [Step N]

Progesterone of the formula (IE, 31.5 g, 100 mmol) was dissolved in anhydrous dichloromethane (300 ml) at -78 ° C and then 1.0 M diisobutylaluminum hydride (DIBAL-H) in hexane (220 ml) was carefully added. The reaction proceeds at the same temperature for 2 hours, after which the reaction mixture is heated to -20 ° C, ethyl acetate (5 ml) is added and stirred for another 20 minutes. The reaction mixture was heated to 0 ° C and the excess of the reducing reagent was removed by slowly adding distilled water (1 ml). The organic layer was extracted with 10% sulfuric acid, washed again with distilled water and dried over magnesium sulfate. It was then filtered and evaporated under reduced pressure to obtain the title compound (30.6 g, 96% yield).

Example 30. Synthesis of 20-hydroxy-4-pregnen-3-one of formula (I-E-2) from a compound of formula (I-E-1) [Step O]

The compound of formula (IE-1, 30 g, 94 mmol) is dissolved in dichloromethane (300 ml) at room temperature and then activated manganese oxide (81 g, 940 mmol) is immediately added. The reaction mixture is heated to 40 ° C, then stirred vigorously for 2 hours. After completion of the reaction, in order to remove manganese oxide, the reaction mixture was passed through a flash column with silica. The solvent was removed by evaporation under reduced pressure to obtain the title compound (27.4 g, yield 92%).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.74 (s, 1H), 3.74 (d, 1H), 2.40-0.79 (bulk of the steroid molecule, and 1.20 (s, 3H) ), 1.15 (d, 3H), 0.82 (s, 3H) = 30H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 200.0, 171.8, 124.2, 70.9, 58.8, 55.8, 54.2, 42.8, 40.1, 39.0, 36.1, 35.9, 34.4, 33.3, 32.5, 26.0, 24.8, 24.1, 21.3, 17.8, 12.8.

Example 31. Synthesis of 20-hydroxy-4-pregnen-3-one of formula (I-E-2) from a compound of formula (I-E-1) [Step O]

The compound of formula (IE-1, 30 g, 94 mmol) is dissolved in dichloromethane (300 ml) at room temperature and then activated manganese oxide (163 g, 1.88 mol) is immediately added. The reaction mixture was heated to 40 ° C, then stirred vigorously for 1 hour. After completion of the reaction, in order to remove manganese oxide, the reaction mixture was passed through a flash column with silica. The solvent was removed by evaporation under reduced pressure to obtain the title compound (28.6 g, 96% yield).

Example 32. Synthesis of 20- (p-toluenesulfonyl) -4-pregnen-3-one of formula (I-E-3) from a compound of formula (I-E-2) [Step P]

The compound of formula (I-E-2, 28 g, 88.5 mmol) and N, N-dimethylaminopyridine (DMAP, 21.6 g, 177 mmol) are dissolved in anhydrous dichloromethane (350 ml) at 0 ° C, then slowly added p-toluenesulfonyl chloride (TsCl, 25.3 g, 133 mmol). The reaction mixture was warmed to room temperature, then stirred for 4 hours. The completion of the reaction was confirmed by TLC, then the organic layer was extracted with an aqueous solution of ammonium chloride (150 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (35.8 g, 86% yield).

¹ H-NMR (300 MHz, CDCl ₃ ): 7.79 (d, 2H), 7.32 (d, 2H), 5.74 (s, 1H), 4.15 (d, 1H), 2, 45-0.80 (the bulk of the steroid molecule and 1.15 (s, 3H), 0.83 (s, 3H) = 32H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 200.0, 171.2, 144.7, 130.1, 130.1, 127.9, 126.9, 124.2, 82.6, 56.0, 55.7, 54.1, 42.6, 39.0, 38.6, 36.1, 35.9, 34.4, 33.2, 32.4, 25.8, 24, 4, 22.0, 21.9, 21.2, 20.9, 17.8, 12.2.

Example 33. Synthesis of 20- (methanesulfonyl) -4-pregnen-3-one of formula (I-E-3) from a compound of formula (I-E-2) [Step P]

The compound of formula (I-E-2, 28 g, 88.5 mmol) and triethylamine (TEM) (17 ml, 124 mmol) are dissolved in anhydrous dichloromethane (250 ml) at 0 ° C, then methanesulfonyl chloride (MsCl, 8) is slowly added. 2 ml, 106 mmol). The reaction mixture is warmed to room temperature at which the reaction takes 4 hours. After completion of the reaction, the organic layer was extracted with an aqueous solution of ammonium chloride (NH ₄ Cl) (100 ml). The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to obtain the title compound (33.2 g, 95% yield).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.74 (s, 1H), 4.12 (d, 1H), 3.07 (s, 3H), 2.45-0.80 (bulk of the molecule steroid and 1.18 (s, 3H), 1.03 (d, 3H), 0.95 (s, 3H) = 29H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 200.0, 171.2, 144.7, 130.1, 130.1, 127.9, 126.9, 124.2, 82.6, 56.0, 55.7, 54.1, 42.6, 39.0, 38.6, 36.1, 35.9, 34.4, 33.2, 32.4, 25.8, 24, 4, 22.0, 21.9, 21.2, 20.9, 17.8, 12.2.

Example 34. Synthesis of cis, trans-mixture of 4.17 (20) -pregnadiene-3-one of formula (I-E-4) from the compound of formula (I-E-3) [Step Q]

The compound of the formula (IE-3, -Ots, 35 g, 74 mmol) is dissolved in pyridine (100 ml) at room temperature. The reaction mixture was heated at 120 ° C under reflux for 3 hours. After completion of the reaction, pyridine is removed under reduced pressure. The resulting residue was dissolved in ethyl acetate (150 ml) and washed with 1 N. HCl solution. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (21.4 g, yield 97%).

¹ H-NMR (300 MHz, CDCl ₃ ): 5.74 (s, 1H), 5.14 (q, 1H), 2.44-0.8 (bulk of the steroid molecule and 1.71 (d, 3H) ), 1.23 (s, 3H), 0.93 (s, 3H) = 28H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 199.9, 171.7, 150.0, 124.21, 114.1, 56.0, 54.2, 44.5, 39.0, 37.2, 36.1, 35.5, 34.4, 33.3, 32.3, 31.7, 24.8, 21.6, 17.7, 17.2, 13.5.

Example 35. Synthesis of a mixture of the cis and trans isomers of 4.17 (20) -pregnadien-3-one of the formula (I-E-4) from the compound of the formula (I-E-3) [Step Q]

The compound of the formula (IE-3, -Ots, 17.5 g, 37 mmol) is dissolved in absolute methanol (80 ml) at room temperature. Sodium methoxide (6 g, 111 mmol) was added to the resulting solution, and the reaction mixture was heated under reflux for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure. The reaction mixture was dissolved in ethyl acetate (100 ml) and washed with brine. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (10.1 g, yield 91%).

Example 36. Synthesis of a mixture of the cis and trans isomers of 4.17 (20) -pregnadien-3-one of the formula (I-E-4) from the compound of the formula (I-E-3) [Step Q]

The compound of the formula (IE-3, -Oms, 20 g, 51 mmol) is dissolved in pyridine (80 ml) at room temperature. The reaction mixture was heated at 120 ° C. under reflux for 2 hours. After completion of the reaction, pyridine is removed under reduced pressure. The resulting reaction mixture was dissolved in ethyl acetate (100 ml) and washed with 1 N. HCl solution. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (14.5 g, 95% yield).

Example 37. Synthesis of a mixture of cis and trans isomers of 4.17 (20) -pregnadien-3-one of formula (I-E-4) from a compound of formula (I-E-3) [Step Q]

The compound of the formula (IE-3, -Oms, 10 g, 25.5 mmol) is dissolved in absolute methanol (80 ml) at room temperature. Sodium methoxide (5.5 g, 102 mmol) was added to the resulting solution, and the reaction mixture was heated under reflux for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with brine. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (7.1 g, yield 93%).

Example 38. Synthesis of E-guggulsterone [4.17 (20) -E-pregnadiene-3.16-dione] of formula (III) from the compound of formula (II-A) [Step R]

E-Guggulsterol (22 g, 70 mmol) of formula (II-A) was dissolved in dichloromethane (200 ml) at room temperature. Activated manganese dioxide (MnO ₂ , 60 g, 700 mmol) is immediately added to the resulting solution and then stirred vigorously for 2 hours. After completion of the reaction, excess manganese dioxide is removed by filtration. The solvent was evaporated under reduced pressure to obtain the title compound (20.6 g, yield 94%).

¹ H-NMR (300 MHz, CDCl ₃ ): 6.52 (q, 1H), 5.76 (s, 1H), 2.50-1.08 (bulk of the steroid molecule, and 1.89 (d, 3H) ), 1.25 (s, 3H), 1.08 (s, 3H) = 26H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 206, 199.6, 170.5, 147.8, 129.9, 124.5, 53.8, 49.9, 43.5, 39, 0, 38.2, 36.4, 35.9, 34.7, 34.3, 32.9, 32.2, 21.1, 17.9, 17.7, 13.6.

Example 39. Synthesis of E-guggulsterone [4.17 (20) -E-pregnadiene-3.16-dione] of formula (III) from a compound of formula (II-A) [Step R]

E-Guggulsterol (22 g, 70 mmol) of formula (II-A) was dissolved in dichloromethane (300 ml) at room temperature. Activated manganese dioxide (MnO ₂ , 120 g, 1.4 mol) was immediately added to the resulting solution and stirred vigorously for 1 hour. After completion of the reaction, excess manganese dioxide is removed by filtration. The solvent was evaporated under reduced pressure to obtain the title compound (21.4 g, yield 98%).

Example 40. Synthesis of E-guggulsterone [4.17 (20) -E-pregnadiene-3.16-dione] of formula (III) from a compound of formula (II-B) [Step S]

The compound of formula (II-B, 25 g, 79 mmol) is dissolved in benzene (200 ml) at room temperature. Cyclohexanone (82 ml) and aluminum isopropoxide (8.1 g, 40 mmol) are added to the resulting solution in order. The reaction mixture was heated at 80 ° C. under reflux for 2 hours. After the reaction mixture was cooled to room temperature, a 10% aqueous solution of sulfuric acid (50 ml) was added, then it was vigorously stirred at room temperature for 15 minutes. The benzene layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (150 ml). The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (22.8 g, yield 92%, individual E-guggulsterone).

¹ H-NMR (300 MHz, CDCl ₃ ): 6.52 (q, 1H), 5.76 (s, 1H), 2.50-1.08 (bulk of the steroid molecule, and 1.89 (d, 3H) ), 1.25 (s, 3H), 1.08 (s, 3H) = 26H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 206, 199.6, 170.5, 147.8, 129.9, 124.5, 53.8, 49.9, 43.5, 39, 0, 38.2, 36.4, 35.9, 34.7, 34.3, 32.9, 32.2, 21.1, 17.9, 17.7, 13.6.

Example 41. Synthesis of E-guggulsterone [4.17 (20) -E-pregnadiene-3.16-dione] of formula (III) from a compound of formula (II-B) [Step S]

The compound of formula (II-B, 25 g, 79 mmol) is dissolved in toluene (200 ml) at room temperature. Cyclohexanone (82 ml) and aluminum isopropoxide (8.1 g, 40 mmol) are added to the resulting solution in order. The reaction mixture was heated at 120 ° C. under reflux for 2 hours. After the reaction mixture was cooled to room temperature, a 10% aqueous solution of sulfuric acid (50 ml) was added, then it was vigorously stirred at room temperature for 15 minutes. The toluene layer was separated and the remaining aqueous layer was extracted with ethyl acetate (150 ml). The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (23.3 g, yield 94%, guggulsterone E: Z = 7: 3).

Example 42. Synthesis of E-guggulsterone [4.17 (20) -E-pregnadiene-3.16-dione] of formula (III) from a compound of formula (II-B) [Step S]

The compound of formula (II-B, 25 g, 79 mmol) is dissolved in toluene (200 ml) at room temperature. Cyclohexanone (82 ml) and aluminum sec-butoxide (10 g, 40 mmol) are added in order to the resulting solution. The reaction mixture was heated at 120 ° C. under reflux for 2 hours. After the reaction mixture was cooled to room temperature, a 10% aqueous solution of sulfuric acid (50 ml) was added, then it was vigorously stirred at room temperature for 15 minutes. The toluene layer was separated and the remaining aqueous layer was extracted with ethyl acetate (150 ml). The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (22.5 g, yield 91%, guggulsterone E: Z = 3: 1).

Example 43. Synthesis of E-guggulsterone [4.17 (20) -E-pregnadiene-3.16-dione] of formula (III) from a compound of formula (II-B) [Step S]

The compound of formula (II-B, 8.3 g, 26 mmol) is dissolved in benzene (100 ml) at room temperature. Methyl ethyl ketone (60 ml) and aluminum isopropoxide (3 g, 13 mmol) are successively added to the resulting solution. The reaction mixture was heated at 80 ° C under reflux for 4 hours. After the reaction mixture was cooled to room temperature, a 10% aqueous solution of sulfuric acid (15 ml) was added and then vigorously stirred at room temperature for 15 minutes. The benzene layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (2.6 g, 32% yield, individual E-guggulsterone).

Example 44. Synthesis of Z-guggulsterone [4.17 (20) -Z-pregnadiene-3.16-dione] of formula (IV) from a compound of formula (III) [Step T]

E-Guggulsterol (1 g, 3.2 mmol) of formula (III) was dissolved in dichloromethane (20 ml) at room temperature, and then methylene blue (5 mg) was dissolved in the resulting solution. The reaction mixture was cooled to 0 ° C and irradiated with a 300 W tungsten lamp for 6 hours. The resulting mixture was passed through a flash column of silica and the solvent was removed by evaporation under reduced pressure. The residue was chromatographed on silica, eluting with ethyl acetate / hexane (v / v = 3/7), to give the title compound (433 mg, 43.3% yield), and unreacted E-guggulsterone (560 mg) was regenerated.

¹ H-NMR (300 MHz, CDCl ₃ ): 5.73 (m, 2H), 2.43-0.75 (bulk of the steroid molecule and 2.08 (d, 3H), 1.22 (s, 3H ), 0.96 (s, 3H) = 26H).

¹³ C-NMR (75.5 MHz, CDCl ₃ ): 208.2, 199.6, 170.7, 148.2, 130.9, 124.5, 54.0, 49.4, 43.4, 39.7, 39.1, 35.9, 35.0, 34.3, 33.0, 32.2, 21.0, 19.9, 17.7, 14.5.

Example 45. Synthesis of Z-guggulsterone [4.17 (20) -Z-pregnadiene-3.16-dione] of formula (IV) from a compound of formula (III) [Step T]

E-Guggulsterol (1 g, 3.2 mmol) of formula (III) was dissolved in toluene (100 ml) at room temperature. The reaction vessel was purged with nitrogen gas and completely plugged. The reaction mixture was kept at 160 ° C for 2 hours, then cooled to room temperature. The solvent is removed under reduced pressure. The resulting mixture was chromatographed on silica, eluting with ethyl acetate / hexane (v / v = 3/7), to give the title compound (586 mg, 58.6% yield), and unreacted E-guggulsterone (410 mg) was regenerated .

Example 46. Synthesis of Z-guggulsterone [4.17 (20) -Z-pregnadiene-3.16-dione] of formula (IV) from a compound of formula (III) [Step T]

E-Guggulsterol (1 g, 3.2 mmol) of formula (III) was dissolved in benzene (100 ml) with p-toluenesulfonic acid (100 mg) at room temperature. The reaction mixture was heated at 80 ° C under reflux for 1 hour, cooled to room temperature, then evaporated under reduced pressure. The resulting mixture was chromatographed on silica, eluting with ethyl acetate / hexane (v / v = 3/7) to give the title compound (664 mg, 64.4% yield), and unreacted E-guggulsterone (350 mg) was regenerated .

INDUSTRIAL APPLICATION

In accordance with the present invention, cheap 4.17 (20) -E-pregnadiene-3.16-dione (E-guggulsterone) of formula (III) and its enantiomer, 4.17 (20) -Z-pregnadiene can be obtained in high yield. -3,16-dione (Z-guggulsterone) of the formula (IV), which effectively reduce elevated low density lipoprotein (LDL) and high cholesterol, and also increase low levels of high density lipoprotein (HDL).

Claims (8)

1. The method of obtaining 4.17 (20) -Z-pregnadiene-3,16-dione of the following formula (IV), comprising oxidizing a compound of the following formula (II) using pyridinium chlorochromate, pyridinium dichromate, Jones reagent, MnO ₂ , aluminum isopropoxide, aluminum tributoxide or aluminum phenoxide to obtain 4.17 (20) -E-pregnadiene-3.16-dione of the following formula (III) and processing the resulting 4.17 (20) -E-pregnadiene-3.16- dione of the following formula (III) in accordance with any of the reactions selected from the group consisting of a photochemical reaction carried out with using a photosensitizer selected from the group consisting of methylene blue, methylene green and Bengal pink, a thermochemical reaction carried out by heating the solvent, benzene, toluene, xylene or mesitylene, under reflux at 80-200 ° C for a period of time from 1 to 48 hours, and a reaction using an acid catalyst, where the acid catalyst is p-toluenesulfonic acid or 0.1-3.0 N. HCl.

where C is a hydroxyl group (—OH) or an oxo group (= O), and the dotted line indicates the presence of a double bond at position C-4 or C-5. 2. The method according to claim 1, where the acid catalyst is p-toluenesulfonic acid. 3. A method of obtaining a compound of formula (II) described in claim 1, comprising protecting the 3-keto group of a compound of formula (IA) with 1,2-ethanedithiol to obtain a compound of formula (IA-1), a Wittig reaction involving the obtained compound of formula (IA -1) to obtain a compound of formula (IA-2), removing the protective group to obtain a compound of formula (IA-3) and reacting the obtained compound with selenium dioxide (SeO ₂ ) in the presence of peroxide.

4. A method of obtaining a compound of formula (II) described in claim 1, comprising a Wittig reaction involving a compound of formula (IB) to obtain a compound of formula (IB-1) and reacting a compound of formula (IB-1) with selenium dioxide (SeO ₂ ) in the presence of peroxide.

5. A method of obtaining a compound of formula (II) described in claim 1, comprising a Wittig reaction involving a compound of formula (IB) to obtain a compound of formula (IB-1), oxidizing the resulting compound with pyridinium chlorochromate (PCC) to obtain a compound of formula (IB -2), reacting the obtained compound in the presence of a base to obtain a compound of formula (IB-3) and reacting this product with selenium dioxide in the presence of peroxide.

6. A method of obtaining a compound of formula (II) described in claim 1, comprising protecting the 3-keto group of a compound of formula (IC) with 1,2-ethanediol in the presence of an acid catalyst to obtain a compound of formula (IC-1), the Wittig reaction involving the obtained compounds and ethyltriphenylphosphonium halide in the presence of a strong base to obtain a compound of formula (IC-3), deprotecting the ketone group of a compound of formula (IC-3) to obtain a compound of formula (IA-3) and oxidizing the resulting product with selenium dioxide in the presence of peroxide.

7. A method of obtaining a compound of formula (II) described in claim 1, comprising reacting a compound of formula (I-D) with hydrazine, the purity of which is more than 95%, in the presence of a base at 160 ° C for 2 hours.

8. A method for producing a compound of formula (II) described in claim 1, comprising reducing a compound of formula (1-E) using hydrides in an alcohol solvent to obtain a compound of formula (IE-1), oxidizing the resulting compound using a selective oxidizing reagent MnO ₂ in pentane, hexane, heptane, petroleum ether, benzene, toluene, xylene, acetone, chloroform, dichloromethane or tetrachloroethane to obtain the compound of formula (IE-2), the introduction of a p-toluenesulfonyl group or methanesulfonyl group in the obtained compound another formula (IE-2) to give a compound of formula (IE-3), reacting the obtained product with a base to give a compound of formula (IE-4), and reacting a compound of formula (IE-4) with selenium dioxide.