KR100543533B1 - Method for preparing 4,17 (20) -prostadiene-3,16-dione from 5-androsten-3β-ol-17-one and intermediates for preparing the same - Google Patents

Abstract

The present invention effectively lowers human low density lipoprotein (LDL) and cholesterol levels from 5-androsten-3β-ol-17-one (Dehydroepiandrosterone (DHEA)) and high density lipoprotein (HDL). 4,17 (20) -E -prostadiene-3,16-dione ( E- Guggulsterone; E -gugulsterone) represented by general formula (IV) known to increase the 4,17 (20) -Z -prostadiene-3,16-dione ( Z- Guggulsterone; Z -Gugulsterone) provides a method for producing. Formulas (VI) and (VIII), which are intermediates in the process of the invention, are novel substances.

Description

Method for preparing 4,17 (20) -prostadiene-3,16-dione from 5-androsten-3β-ol-17-one and an intermediate for preparing the same {PROCESS FOR PREPARING 4,17 (20) -PROSTADIEN -3,16-DIONE FROM 5-ANDROSTEN-3β-OL-17-ONE AND THE INTERMEDIATE COMPOUNDS FOR PREPARING THE SAME}

The present invention refers to 4,17 (20) -prostadiene-3,16-dione (Guggulsterone; hereinafter “gugulsterone”) using 5-androsten-3β-ol-17-one (I) as a starting material. the selective preparation of the E isomer and Z isomer) and 4,17 (20) - E - androsta-3-one stent -16 ol (Guggulsterol;. Preparation of this production method and hereinafter) referred to as "gugul sterols". It relates to an intermediate composite for. More specifically, the present invention is directed to the low and high density lipoprotein (LDL) and cholesterol levels that cause hyperlipidemia in humans, and to the high density lipoprotein (HDL) of E and Z -gugulsterone. It relates to a compound represented by the general formula (VI) and (VIII), which is an optional preparation method and an intermediate for preparing the same.

Gugulsterone has been extracted from guggulu trees (Communphora mukul ) in India and has been used as a traditional antihyperlipidemic drug, and recently it is an effective antagonist of farnesoid orphan receptors (FXRs) involved in human cholesterol metabolism. ( Nature , 2002, Jun . , 411., Science , 2002, May, 1703). The existing route of treatment for oral use of gugulsterone was obtained from natural guggulu extract or by using E or Z type gugulsterone through separation and purification using HPLC. A process for the preparation of gugulsterone mixtures using synthesis is disclosed in patent publication EP 0 447 706 A1. The method was performed by reducing ketone and acetate groups with lithium aluminum hydride (LiAlH ₄ ) using 16-dihydropregnalone acetate (1) as a starting material, as shown in the following reaction scheme, to give 5,16-pregnadiene-3β, 20-diol (2) was prepared and reacted with acetic anhydride and p -toluenesulfonic acid to mix 5,17 (20) -trans-prignadiene-3β, 16β and 3β, 16α diacetate (3). Got it. Again from reaction mixture (3) with potassium hydroxide in methanol to give 5,17 (20) -trans-prignadiene-3β, 16β and 3β, 16αdiol (4) in the form of a mixture, which is either aluminum isobutoxide or aluminum phenoxy Oxidation with seeds discloses the synthesis of a gugulsterone mixture with a Z: E ratio of 80:20.

The compound (5) has the following drawbacks in the synthesis method compared to its effectiveness. In other words,

1) Since 16-dihydropregnalone acetate (1) used as a reaction starting material is not a relatively common steroid, it is difficult to industrialize.

2) Lithium aluminum hydride used in the first reduction reaction step (i) generates hydrogen gas when exposed to moisture, which is explosive and therefore dangerous for general industrial processes.

3) The acetic acid solvent used in the second reaction step (ii) has a great difficulty in treating the waste liquid after the completion of the reaction, the reaction time is very long as 72 hours, and the reaction yield is relatively low as 80%.

4) In the third reaction step (iii), the heating reaction time using methanol and potassium hydroxide is 6 hours, which is relatively long.

5) The patent states that the third reaction yield is obtained at 114%, and the yield of the final gugulsterone synthesis step is not specified in the patent.

6) The prepared gugulsterone is obtained in an E- , Z -mixture state ( Z : E = 80: 20).

7) The reliability of patented synthesis is inferior because no instrumental analysis data for gugulsterone and synthetic intermediates are specified.

Therefore, the method described in the above documents cannot be repeated, and since it is not a method for easily and economically preparing Z or E single gugulsterone, the emergence of a method more reliable than this method is urgently needed. Has been required.

It is an object of the present invention to prepare single E form of gugulsterone (IV) in high yield, economically, in a short reaction time, from a readily available, inexpensive 5-androsten-3β-ol-17-one starting material. To provide a way.

It is another object of the present invention to provide a method for preparing the isoform of the Z- type gugulsterone (V) from the E- type gugulsterone (IV).

A further object of the invention is to provide a method for producing intermediates (VI) and gugul sterol (VIII) for producing a stacking gugul Ron (V) of the stacking gugul Ron (IV) or Z form of the E form.

In view of the above facts, the present inventors have diligently studied the synthesis of gugulsterone from 5-androsten-3β-ol-17-one of general formula (I), which is a useful steroid, as shown in the following scheme. It was completed.

In the present invention, 5-androsten-3β-ol-17-one (5-androsten-3β-ol-17-one) is used as a starting material, and the C-17 position of the alcohol is not protected. By wittig reaction of only the ketone, a compound of formula (II) of carbon-carbon ethyl double bond (C = CH-CH ₃ ) was obtained. From this, the synthesis of gugulsterone through two reaction pathways was completed.

Reaction route (1) reacted a compound of formula (II) obtained from Wittig reaction with selenium dioxide (SeO ₂ ) to introduce a hydroxyl group at the C-16 position to obtain a compound of formula (III), Single form E -gugulsterone of general formula (IV) was obtained by oxidation with aluminum isopropoxide without separation. Again, it was found that Z -gugulsterone of general formula (V) was obtained using photoreaction, thermal reaction, or acid catalyst, and completed the invention of reaction route (1) in the reaction formula.

Reaction route (2) is an oxidation reaction using pyridinium chlorochromate (PCC) from a compound of formula (II) to form a compound of formula (VI) by introducing a ketone group at the C-3 position and reacting it with a base. Formula (VII) was synthesized. Subsequently, an oxidizing reaction using a hydroxy group with selenium dioxide (SeO ₂ ) at the C-16 position was performed to produce Gugulsterol of Formula (VIII). The reaction was found to yield a single form E -gugulsterone of general formula (IV), completing the invention of reaction route (2).

That is, the present invention provides a method for preparing a compound of formula (II) without a separate protecting group introduction reaction from the compound of formula (I).

The present invention also provides a method for preparing a compound of formula (III) using a selective oxidant as a catalyst from a compound of formula (II).

The present invention also provides a method for preparing a single E -gugulsterone of general formula (IV) through an oxidation reaction from a compound of general formula (III).

The present invention also provides a method for preparing Z -gugulsterone of general formula (V) using a photoreaction or thermal reaction or an acid catalyst from a single E -gugulsterone of general formula (IV). .

The present invention also provides a process for preparing general formula (VI) using a chromium oxidant from a compound of general formula (II).

The present invention also provides a process for preparing general formula (VII) using a base from a compound of general formula (VI).

The present invention also provides a process for preparing gugulsterol of formula (VIII) using a selenium oxidizing agent from a compound of formula (VII).

The present invention also provides a method for preparing a single form E- gurulsterone of general formula (IV) using manganese oxidizing agent from gugulsterol of general formula (VIII).

Also, in the above reaction formulas (VI) and (VIII) are novel compounds.

Accordingly, the present invention also provides novel compounds useful as intermediates for preparing E- and Z- gugulsterone.

In the manufacturing method of this invention, the general formula (I) compound used as a raw material is an industrially easy thing as a well-known compound.

EMBODIMENT OF THE INVENTION Below, the manufacturing method of this invention is demonstrated in detail.

[Step A] Preparation of the compound represented by general formula (II).

In order to obtain a compound represented by formula (II), ethyltriphenylphosphonium bromide (Ph ₃ P ⁺ CH _{2) in an} anhydrous solvent was added to the C-3 position of the compound represented by formula (I) without an additional protecting group reaction. CH ₃ Br ^-) and may be reacted with a strong base.

As the anhydrous solvent used in this step, one solvent such as diethyl ether, tetrahydrofuran, dimethyl sulfoxide, benzene, toluene, xylene, or a mixture of two or more solvents is used. Among them, the most preferred solvents are tetrahydrofuran and dimethyl sulfoxide solvent.

Wittig reaction are ethyl triphenylphosphonium halide to be used is ethyl triphenyl phosphonium chloride ^{_{(Ph 3 P + CH 2 CH}} 3 Cl -), ethyl triphenyl phosphonium bromide ^{_{(Ph 3 P + CH 2 CH}} 3 Br - ), ethyl triphenyl phosphonium iodide ^{_{(Ph 3 P + CH 2 CH}} 3 I -) , and the double-ethyl triphenyl phosphonium bromide and ethyl triphenyl phosphonium iodide is most preferred. The amount of ethyltriphenylphosphonium halide to be used is generally 1 to 5 equivalents based on general formula (I), preferably 1.5 to 3 equivalents.

Strong base reagents used include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride or hydrides of alkaline earth metals such as lithium hydride, sodium hydride and potassium hydride, n-butyllithium, sec-butyllithium and tert-butyllithium And alkoxides of alkali metals or alkaline earth metals such as lower alkyl metal salts of sodium, sodium methoxide, sodium ethoxide and potassium-t-butoxide. Among the most preferred bases are sodium hydride, n-butyllithium, potassium-t-butoxide. The amount of base used in the reaction is generally 1 to 4 equivalents based on the amount of ethyl triphenylphosphonium bromide forming ylide, and preferably 1 to 1.2 equivalents.

The reaction temperature may vary depending on the solvent used but is usually -10 to 120 ° C, preferably -10 when the ethyltriphenylphosphonium bromide and the strong base are reacted in an anhydrous solvent to form an illide. The temperature which reacts at -20 degreeC and performs Wittig reaction with the compound of General formula (I) is synthesize | combined at the temperature from -10 degreeC to the boiling point of the solvent used. Preferably, the solvent is 25 to 40 ° C. for tetrahydrofuran and 25 to 80 ° C. for dimethyl sulfoxide. The reaction time may vary depending on the reaction temperature and the solvent used, but is usually carried out at 30 minutes to 1 day, preferably at 2 hours or less.

[Step B] Preparation of a compound represented by general formula (III).

The compound represented by general formula (III) is a method of producing by reacting selenium oxide and peroxide in a solvent from a compound of general formula (II).

Selenium dioxide was used as selenium oxide, and the amount of selenium dioxide used in the reaction was generally used in an amount of 0.1 to 3.0 equivalents based on the compound of formula (II), and most preferably 0.5 to 1.5 equivalents.

Peroxides used in the reaction include hydrogen peroxide (H ₂ O ₂ ), t-butylperoxide (t-BuOOH), N -methylmorpholine- N -oxide (NMO), pyridine N-oxide (C ₅ H ₅ NO) and the like, of which t-butylperoxide is most preferred. Usually, the amount of the hydrogen peroxide used in the reaction is used in the amount of 0.5 to 5.0 equivalents, and most preferably 2.0 to 3.0 equivalents, based on the compound of the general formula (II).

As the aprotic polar solvent used in this step, N , N -dimethylformamide, N , N -dimethylacetamide, dimethyl sulfoxide, pyridine, acetonitrile, acetone, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane and the like are used. Can be mentioned. Examples of the ethers include tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, and the like. Examples of the aromatic hydrocarbons include benzene, toluene, xylene and the like. As the solvent used in these, an aprotic polar solvent and ether are preferable, and dichloromethane and dioxane are more preferable.

The reaction temperature may vary depending on the solvent used, but is usually -10 to 80 ° C, preferably -10 to 10 ° C. The reaction time may vary depending on the reaction temperature and the solvent used, but is usually carried out at 30 minutes to 12 hours, preferably 2 hours or less.

[Step C] represented by General Formula (IV) E Preparation of Gugulsterone.

Gugulsterone represented by formula (IV) is obtained by the Oppenauer oxidation reaction using a compound represented by formula (III) and an aluminum oxidizer.

Examples of aluminum oxidants used in the oppenauer oxidation process include aluminum isopropoxide (Al [OCH (CH ₃ ) ₂ ] ₃ ), aluminum tri sec -butoxide (Al [OCH (CH ₃ ) CH ₂ CH ₃ ] ₃ ), aluminum tri tert -butoxide (Al [OC (CH ₃ ) ₃ ] ₃ ), aluminum phenoxide (Al [OC ₆ H ₅ ] ₃ ), and the like, most preferably aluminum isopropoxy De is the best. The amount of aluminum oxidant to be used is generally 0.3 to 1.5 equivalents based on General Formula (III), and most preferably 0.5 to 1 equivalent.

As the anhydrous solvent used in this process, benzene solvents such as benzene, toluene, xylene, and mesitylene are used, and most preferably benzene and toluene.

Acetone, ethyl methyl ketone, acetophenone, benzophenone, cyclohexanone, cycloheptanone and the like are used as ketones used as a reducing agent in the reaction in the oppenauer oxidation reaction. Among them, acetone and cyclohexanone are most preferred. .

The reaction temperature may vary depending on the solvent used, but is usually reacted at 50 to 180 ° C. The reaction temperature affects the isomerization of the target compound, gugulsterone. When the reaction temperature is 50-100 ° C, a single E -gugulsterone is produced, and when reacted at 120-180 ° C, E- , Z Obtained in the form of a gugulsterone mixture. The reaction time may vary depending on the reaction temperature and the reagent used, but it is usually best to carry out the reaction at 30 minutes to 4 hours, preferably 2 hours or less.

[Process D] represented by General Formula (V) Z Preparation of Gugulsterone.

Z -gugulsterone represented by general formula (V) is obtained by photoreaction or thermal reaction or acid catalysis from E -gugulsterone represented by general formula (IV).

Methylene blue, methylene green, rose bengal, etc. are used as the photocatalyst used in the isomerization reaction of E -gugulsterone by photoreaction, and the amount of use is generally 0.01 to 0.2 equivalents based on general formula (IV). It is used and most preferably 0.05-0.1 equivalent.

As a solvent used in the photoreaction process, a mixed solvent in which a single solvent such as distilled water, methanol, ethanol, acetonitrile, acetone, carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene is combined with at least two solvents. Use As the solvent used in these, dichloromethane, chloroform, acetonitrile, methanol and ethanol are preferable, and chloroform and methanol are more preferable.

The reaction temperature may vary depending on the solvent used, but is usually -10 to 100 ° C, and most preferably 20 to 50 ° C. The reaction time may vary depending on the reaction temperature and the photocatalyst used, but it is usually best to carry out the reaction at 1 hour to 48 hours, preferably 10 hours or less.

As a solvent used in a thermal reaction process, solvents, such as benzene, toluene, xylene, and mesitylene, are used. Among them, toluene is most preferred.

The reaction temperature may vary depending on the solvent used, but is usually 80 to 200 ° C, and most preferably 100 to 160 ° C. The reaction time may vary depending on the reaction temperature and the solvent used, but it is usually best to carry out the reaction at 1 hour to 48 hours, preferably 2 hours or less.

P -toluenesulfonic acid was used as the acid catalyst used in the isomerization reaction of E -gugulsterone by the acid catalysis, and the amount used was generally 0.01 to 0.5 equivalents based on general formula (IV), and most preferably, Is 0.05 to 0.2 equivalents.

As the solvent used in the acid catalysis step, a mixed solvent in which a single solvent such as acetonitrile, acetone, carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, xylene, and two or more solvents are combined. As the solvent used in these, dichloromethane, chloroform, acetonitrile, benzene and toluene are preferable, and chloroform and benzene are more preferable.

The reaction temperature may vary depending on the solvent used, but is usually -10 to 160 ° C, and most preferably 30 to 80 ° C. The reaction time may vary depending on the reaction temperature and the amount of acid catalyst used, but it is usually best to carry out the reaction at 1 hour to 10 hours, preferably 2 hours or less.

[Step E] Preparation of a compound represented by general formula (VI).

The compound represented by general formula (VI) is a method of manufacturing general compound (II) by making it react with an oxidizing agent.

In this process, oxidization of the general C-3 secondary alcohol to ketone is performed by using chromium oxidants such as pyridinium chloro chromate (PCC), pyridinium dichromate (PDC) and Jones reagent, and Swern. Oxidation reaction (DMSO + ClCOCOCl) is used, and pyridinium chlorochromate oxidation is the most suitable oxidation method.

The solvent used in this process is dichloromethane for pyridinium chlorochromate (PCC), N , N -dimethylacetamide for pyridinium dichromate (PDC), acetone for Jones reagent, and Swern depending on the type of oxidant. For the oxidation reaction, it is preferable to use dichloromethane.

The amount of oxidant to be used varies depending on the oxidizing agent, but in the case of chromium oxidizer, it is usually used 1 to 5 equivalents based on the amount of the general formula (II), most preferably 1.2 to 2.0 equivalents. In the Swern oxidation reaction, it is preferable to use 1 to 3 equivalents of dimethyl sulfoxide and 1 to 1.5 equivalents of oxalyl chloride in the synthesis of oxidant.

The reaction temperature may vary depending on the oxidizing agent used, but is usually -78 to 30 ° C, preferably -10 to 10 ° C for chromium oxidant, and -78 to -30 ° C for Swern oxidation. Do. The reaction time may vary depending on the oxidation method, but is usually carried out in 30 minutes to 12 hours, preferably 2 hours or less.

[Step F] Preparation of the compound represented by general formula (VII).

The compound represented by the general formula (VII) is obtained through a basic reaction from the compound represented by the general formula (VI).

As the solvent used in this step, solvents such as methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, benzene and toluene are used. Among them, the most preferred solvents are methanol and tetrahydrofuran.

Bases used for the α-hydrogen removal reaction of ketones include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, n-butyllithium and sec- Organometallic reagents such as butyllithium and tert-butyllithium, and alkali metal alcohol base reagents such as sodium methoxide, sodium ethoxide and potassium-t-butoxide. Among the most preferred bases are sodium hydroxide, potassium hydroxide and potassium-t-butoxide. The amount of base used for the reaction is generally 1 to 4 equivalents relative to the amount of the general formula (VI), preferably 1 to 1.5 equivalents.

The reaction temperature may vary depending on the base and solvent used, but is usually -10 to 120 ° C, preferably 10 to 50 ° C. The reaction time may vary depending on the reaction temperature, the base used, and the solvent, but the reaction is usually performed at 30 minutes to 4 hours, preferably 1 hour or less.

[Step G] Preparation of gugul sterol represented by general formula (VIII).

Gugulsterol represented by the general formula (VIII) is a method for producing selenium oxide and a hydrogen peroxide compound from a compound of the general formula (VII) by reaction under a solvent.

Selenium dioxide was used as the selenium oxide, and the amount of selenium dioxide used in the reaction was generally used in an amount of 0.1 to 2.0 equivalents based on the compound of formula (VII), and most preferably 0.25 to 1.0 equivalents.

Hydrogen peroxide used in the reaction includes hydrogen peroxide (H ₂ O ₂ ), t-butylperoxide (t-BuOOH), N -methylmorpholine- N -oxide (NMO), pyridine N-oxide (C ₅ H ₅ NO) and the like, of which t-butylperoxide is most preferred. The amount of the hydrogen peroxide used in the reaction is usually used in the amount of 0.5 to 5.0 equivalents, and most preferably 2.0 to 3.0 equivalents, relative to the compound of the general formula (VII).

As the aprotic polar solvent used in this step, N , N -dimethylformamide, N , N -dimethylacetamide, dimethyl sulfoxide, pyridine, acetonitrile, acetone, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane and the like are used. Can be mentioned. Examples of the ethers include tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, and the like. Examples of the aromatic hydrocarbons include benzene, toluene, xylene and the like. As the solvent used in these, an aprotic polar solvent and ether are preferable, and dichloromethane and dioxane are more preferable.

The reaction temperature may vary depending on the solvent used, but is usually -10 to 80 ° C, preferably 10 to 30 ° C. The reaction time may vary depending on the reaction temperature and the solvent used, but is usually carried out at 30 minutes to 12 hours, preferably 2 hours or less.

[Step H] Preparation of Gugulsterone Represented by General Formula (IV)

The gugulsterone represented by the general formula (IV) is obtained by reacting the gugulsterol represented by the general formula (VIII) with an oxidizing agent.

The oxidizing agents used to oxidize common secondary alcohols to ketones in this process include chromium oxidants such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent, and activated manganese dioxide (MnO ₂ ). There is this. Among them, Jones reagent and activated manganese dioxide are suitable for the reaction, and the most suitable oxidant is activated manganese dioxide.

As the solvent used in this step, solvents and solvents such as pentane, hexane, heptane, petroleum ether, benzene, toluene, xylene, dimethyl sulfoxide, acetone, chloroform, dichloromethane, carbon tetrachloride, diethyl ether and tetrahydrofuran are used. Instead of oxidizing with activated manganese dioxide. Of these, the most preferred solvent is dichloromethane.

The amount of oxidant to be used depends on the oxidizing agent, but usually 1 to 20 equivalents is used based on the amount of the general formula (VIII). 5-10 equivalents are preferable for activated manganese dioxide.

The reaction temperature may vary depending on the solvent used, but is usually -10 to 100 ° C, preferably 20 to 50 ° C. The reaction time may vary depending on the reaction temperature and the solvent used, but is usually carried out at 30 minutes to 12 hours, preferably 2 hours or less.

Thus obtained E -gugulsterone of the general formula (IV) and Z -gugulsterone of the general formula (V) are substances having good efficacy as a therapeutic agent for hyperlipidemia in humans.

EXAMPLE

Hereinafter, the method of the present invention will be described in detail with reference to Examples. However, the present invention is not limited to these examples.

Example 1

Preparation of 5,17 (20) -Z-prognadiene-3β-ol of general formula (II) from general formula (I) [Step A]:

130 g (350 mmol) of ethyltriphenylphosphonium bromide is dissolved in 400 mL of anhydrous dimethyl sulfoxide at a reaction temperature of 15 DEG C, and 8.6 g (360 mmol) of sodium hydride are slowly added. After complete dropwise addition, the reaction mixture was allowed to react for another 1 hour at room temperature, and then 28.8 g (100 mmol) of the starting material 5-androsten-3β-ol-17-one of general formula (I) was slowly added at room temperature. The temperature was gradually raised to 80 ° C. for 2 hours, and when the reaction was completed, the mixture was separated and extracted three times with 800 ml of brine and 300 ml of ethyl acetate, and the organic layer was removed with magnesium sulfate. After filtration, the solvent was concentrated in a distillation under reduced pressure, 400 ml of a mixed solution of hexane and ethyl ester (10: 1) was added to precipitate and filtered triphenylphosphinooxide (Ph ₃ P = O) as a by-product. Distillation under reduced pressure gave 28.6 g (yield: 95%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.38 (d, 1H), 5.16 (m, 1H), 3.53 (m, 1H), 2.42 to 0.92 (steroid main-body and 1.70 (d, 3H), 1.04 (s, 3H), 0.92 (s, 3H) = 29H)

¹³ C-NMR (75.5 MHz, CDCl ₃ ) δ: 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 2

Preparation of 5,17 (20) -Z-prognadiene-3β-ol of general formula (II) from general formula (I) [Step A]:

92.8 g (250 mmol) of ethyltriphenylphosphonium bromide are dissolved in 300 ml of anhydrous dimethyl sulfoxide at a reaction temperature of 15 ° C, and 6.3 g (260 mmol) of sodium hydride are slowly added. After complete dropwise addition, the reaction mixture was allowed to react for another 1 hour at room temperature, and then 28.8 g (100 mmol) of the starting material 5-androsten-3β-ol-17-one of general formula (I) was slowly added at room temperature. The temperature was gradually raised to 80 ° C. for 2 hours, and when the reaction was completed, the mixture was separated and extracted three times with 600 ml of brine and 200 ml of ethyl acetate, and the organic layer was removed with magnesium sulfate. After filtration, the solvent was concentrated in a reduced pressure distillation, and then 300 ml of a mixture of hexane and ethyl ester (10: 1) was added to precipitate and filter triphenylphosphinooxide (Ph ₃ P = O) as a by-product, and again. Distillation under reduced pressure afforded 25.5 g (yield: 85%) of the title compound.

Example 3

Preparation of 5,17 (20) -Z-prognadien-3-ol of general formula (II) from general formula (I) [Step A]:

92.8 g (250 mmol) of ethyltriphenylphosphonium bromide were mixed with 300 mL of anhydrous tetrahydrofuran at a reaction temperature of 15 DEG C, and 280 mL (280 mmol) of potassium t-butoxide (1 mmol solution of anhydrous tetrahydrofuran) was added for 15 minutes. Add slowly over. After complete dropwise addition, the reaction mixture was allowed to react for another 1 hour at room temperature, and then 18.2 g (63 mmol) of 5-androstro-3-3-ol-17-one of the general formula (I) as a starting material was slowly added at room temperature. The reaction mixture was heated to reflux for 6 hours, and when the reaction was completed, the solvent was removed under reduced pressure, and 300 ml of a mixed solution of hexane and ethyl ester (10: 1) was added to form a byproduct of triphenylphosphinooxide (Ph ₃ P = O). ) Was precipitated, filtered and distilled under reduced pressure again to obtain 15.7 g (yield: 83%) of the title compound.

Example 4

Preparation of 5,17 (20) -Z -prognadiene-3β, 16α-diol of general formula (III) from general formula (II) [Step B]:

At a reaction temperature of 25 ° C., 36 ml of t-butylperoxide was slowly added while 5.3 g (476 mmol) of selenium dioxide was mixed well with 200 ml of dichloromethane. After 30 minutes, the temperature was lowered to 0 ° C. and a solution of 28.6 g (95.2 mmol) of 5,17 (20) -Z -pregnadiene-3β-ol of formula (II) in 100 ml of dichloromethane was dissolved in 10 minutes. Add slowly over time. The reaction is continued for 3.5 hours at the same temperature. After completion of the reaction, the organic layer was washed with brine and distilled water and water was removed with magnesium sulfate. Filtration through a short silica gel column and distillation under reduced pressure gave 27.4 g (yield: 91%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.60 (q, 1H), 5.38 (s, 1H), 4.46 (s, 1H), 3.55 (m, 1H), 2.30 to 0.91 (steroid main-body and 1.86 (d, 3H), 1.05 (s, 3H), 0.91 (s, 3H) = 28H)

¹³ C-NMR (75.5 MHz, CDCl ₃ ) δ: 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 5

Preparation of 5,17 (20) -Z -prognadiene-3β, 16α-diol of general formula (III) from general formula (II) [Step B]:

At a reaction temperature of 25 ° C., 36 ml of t-butylperoxide was slowly added while 9.2 g (83.2 mmol) of selenium dioxide was mixed well with 250 ml of dichloromethane. After 30 minutes, the temperature was lowered to 0 ° C. and a solution of 25 g (83.2 mmol) of 5,17 (20) -Z -pregnadiene-3β-ol of the general formula (II) in 100 ml of dichloromethane was dissolved in 10 minutes. Add slowly over time. The reaction is continued for 2 hours at the same temperature. After completion of the reaction, the organic layer was washed with brine and distilled water and water was removed with magnesium sulfate. Filtration through a short silica gel column and distillation under reduced pressure afforded 25.8 g (yield: 98%) of the title compound.

Example 6

Preparation of 4,17 (20) -E -prognadiene-3,16-dione ( E -gugulsterone) of general formula (IV) from general formula (III) [Step C]:

At room temperature, 25 g (79 mmol) of 5,17 (20) -E -pregnadiene-3β, 16α-diol of general formula (III) was dissolved in 200 ml of benzene, followed by 82 ml of cyclohexanone and aluminum isopro 8.1 g (40 mmol) of the oxide are added sequentially. The reaction was heated to reflux at 80 ° C. for 1.5 hours, lowered to room temperature, and then 50 ml of 10% aqueous sulfuric acid solution was added thereto, followed by vigorous stirring at room temperature for 15 minutes. The benzene layer is separated and extracted again with 150 ml of ethyl acetate. The organic solvent was dried over magnesium sulfate, filtered and distilled under reduced pressure to obtain 23.5 g (yield: 95%, single E -gugulsterone) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.52 (q, 1H), 5.76 (s, 1H), 2.50 to 1.08 (steroid main-body and 1.89 (d, 3H), 1.25 (s, 3H), 1.08 (s, 3H) = 26H)

¹³ C-NMR (75.5 MHz, CDCl 3) δ : 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 7

Preparation of 4,17 (20) -E -prognadiene-3,16-dione ( E -gugulsterone) of general formula (IV) from general formula (III) [Step C]:

At room temperature, 25 g (79 mmol) of 5,17 (20) -E -pregnadiene-3β, 16α-diol of general formula (III) was dissolved in 200 ml of toluene, followed by 82 ml of cyclohexanone and aluminum isopropoxide. Add 8.1 g (40 mmol) of seeds in sequence. The reaction was heated to reflux at 120 ° C. for 1 hour, cooled to room temperature, 50 ml of 10% aqueous sulfuric acid solution was added, and stirred vigorously at room temperature for 15 minutes. The toluene layer is separated and extracted again with 150 ml of ethyl acetate. All organic solvents were dried over magnesium sulfate, filtered, and distilled under reduced pressure to obtain 23.3 g (yield: 94%, E : Z = 4: 1 gugulsterone) of the title compound.

Example 8

Preparation of 4,17 (20) -E -prognadiene-3,16-dione ( E -gugulsterone) of general formula (IV) from general formula (III) [Step C]:

At room temperature, 25 g (79 mmol) of 5,17 (20) -E -pregnadiene-3β, 16α-diol, which is general formula (III), was dissolved in 200 ml of toluene, followed by 82 ml of cyclohexanone and aluminum tri sec- . 10 g (40 mmol) of butoxide are added sequentially. The reaction was heated to reflux for 2 hours, cooled to room temperature, 50 mL of 10% aqueous sulfuric acid solution was added and vigorously stirred at room temperature for 15 minutes. The toluene layer is separated and extracted again with 150 ml of ethyl acetate. All organic solvents were dried over magnesium sulfate, filtered and distilled under reduced pressure to obtain 22.5 g (yield: 91%, E : Z = 3: 1 gugulsterone) of the title compound.

Example 9

Preparation of 4,17 (20) -E -prognadiene-3,16-dione ( E -gugulsterone) of general formula (IV) from general formula (III) [Step C]:

At room temperature, 8.3 g (26 mmol) of general formula (III) 5,17 (20) -E -pregnadiene-3β, 16α-diol was dissolved in 100 ml of benzene, followed by 60 ml of acetone and aluminum isopropoxide. 3 g (13 mmol) are added sequentially. The reaction is heated to reflux for 7 hours, cooled to room temperature, 15 ml of 10% aqueous sulfuric acid solution is added and vigorously stirred at room temperature for 15 minutes. The benzene layer is separated and extracted again with 50 ml of ethyl acetate. All organic solvents were dried over magnesium sulfate, filtered and distilled under reduced pressure to obtain 2.6 g (yield: 32%, single E -gugulsterone) of the title compound.

Example 10

Preparation of 4,17 (20) -Z -prognadiene-3,16-dione ( Z -gugulsterone) of general formula (V) from general formula (IV) [Step D]:

At room temperature, 1 g (3.2 mmol) of E -gugulsterone of general formula (IV) is dissolved in 20 ml of dichloromethane, and 5 mg of methylene blue is added thereto. The reaction solution is cooled to 0 ° C. and the 300 W tungsten bulb is irradiated for 2 hours. The reaction was filtered through a short silica gel column, the solvent was distilled off under reduced pressure, and then again purified by column with 30% hexane solvent of ethyl acetate to obtain 630 mg (yield: 63%) of the title compound. 345 mg of unreacted E -gugulsterone was recovered. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.73 (m, 2H), 2.43-0.75 (steroid main-body and 2.08 (d, 3H), 1.22 (s, 3H), 0.96 (s, 3H) = 26H )

¹³ C-NMR (75.5 MHz, CDCl ₃ ) δ: 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 11

Preparation of 4,17 (20) -Z -prognadiene-3,16-dione ( Z -gugulsterone) of general formula (V) from general formula (IV) [Step D]:

At room temperature, dissolve 1 g (3.2 mmol) of E -gugulsterone, general formula (IV), in 100 ml of toluene, fill the container with nitrogen, and close completely. To an external temperature of 160 ℃ lower the temperature to room temperature after 2 hours and remove the solvent was evaporated under reduced pressure, and ethyl acetate 30% column with hexane to give the title compound 586 mg (yield: 58.6%) was obtained the unreacted E - gugul Ste 410 mg recovery of the loan.

Example 12

Preparation of 4,17 (20) -Z -prognadiene-3,16-dione ( Z -gugulsterone) of general formula (V) from general formula (IV) [Step D]:

At room temperature, 1 g (3.2 mmol) of E -gugulsterone and 100 mg of p -toluenesulfonic acid are dissolved in 100 ml of benzene, and the reaction solution is heated to reflux at 80 ° C for 1 hour. The reaction was cooled to room temperature and short in a silica gel column filtration, was evaporated under reduced pressure to a rear, back ethyl acetate 30% hexane to the column as solvent the title compound 685 mg (yield: 68.5%) was obtained the unreacted E - the gugul stacking theory 310 mg was recovered.

Example 13

Preparation of 5,17 (20) -Z -pragnadien-3-one of general formula (VI) from general formula (II) [Step E]:

25 g (83 mmol) of general formula (II) 5,17 (20) -Z -pregnadiene-3β-ol was dissolved in 250 ml of dichloromethane at a reaction temperature of 0 ° C, followed by molecular sieves 4. g and 21.5 g (100 mmol) of pyridinium chlorochromate (PCC) are added in sequence. The reaction is carried out for 2 hours while maintaining the temperature, and 250 ml of ethyl ether is added to terminate the reaction. The by-products were filtered off with a short silica gel column, the solvent was removed, and then columned with ethyl acetate 30% hexane solvent to give 22.5 g (yield: 91%) of the title compound.

¹ H-NMR (300MHz, CDCl ₃ ) δ: 5.38 (t, 1H), 5.17 (m, 1H), 3.28 (d, 1H), 2.85 (q, 1H), 2.82 ~ 0.80 (steroid main-body and 1.70 (d, 3H), 1.22 (s, 3H), 0.94 (s, 3H) = 26H)

¹³ C-NMR (75.5 MHz, CDCl ₃ ) δ: 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 14

Preparation of 5,17 (20) -Z -pragnadien-3-one of general formula (VI) from general formula (II) [Step E]:

5.0 g (17 mmol) of General Formula (II) 5,17 (20) -Z -pregnadiene-3β-ol was dissolved in 100 ml of acetone at 10 ° C, and 3 ml of 8 N -Jos reagent was slowly added. do. The reaction is carried out for 30 minutes while maintaining the temperature, and the solvent is distilled off under reduced pressure, followed by extraction with ethyl acetate and brine. The organic layer was dried over magnesium sulfate, filtered, and distilled under reduced pressure, and then purified by column with 30% hexane solvent of ethyl acetate to obtain 3.8 g (yield: 74%) of the title compound.

Example 15

Preparation of 4,17 (20) -Z -pragnadien-3-one of general formula (VII) from general formula (VI) [Step F]:

At room temperature, 22 g (73.7 mmol) of 5,17 (20) -Z -pregnadien-3-one of general formula (VI) is dissolved in 100 ml of methanol, and 5 g of potassium hydroxide is dissolved. The reaction is warmed to reflux for 40 minutes and then cooled to room temperature. The solvent is distilled off under reduced pressure, and extracted with ethyl acetate and brine. The organic layer was dried over magnesium sulfate, filtered and distilled under reduced pressure to obtain 20 g (yield: 91%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.74 (s, 1H), 5.14 (q, 1H), 2.44 to 0.8 (steroid main-body and 1.71 (d, 3H), 1.23 (s, 3H), 0.93 (s, 3H) = 28H)

¹³ C-NMR (75.5 MHz, CDCl 3) δ : 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 16

Preparation of 4,17 (20) -Z -pragnadien-3-one of general formula (VII) from general formula (VI) [Step F]:

At a reaction temperature of 10 ° C., 15 g (50 mmol) of 5,17 (20) -Z -pregnadien-3-one of the general formula (VI) was dissolved in 80 ml of anhydrous tetrahydrofuran and potassium t-butoxide (anhydrous) was added. 60 ml (60 mmol) of tetrahydrofuran 1 mmol solution are slowly added over 15 minutes. After slowly raising the temperature of the reaction to room temperature and reacting for another hour, the solvent was distilled off under reduced pressure, and extracted with ethyl acetate and brine. The organic layer was dried over magnesium sulfate, filtered and distilled under reduced pressure to obtain 14.2 g (yield: 95%) of the title compound.

Example 17

Preparation of 4,17 (20) -E -prognadien-3-one-16α-ol ( E -gugulsterol) of general formula (VIII) from general formula (VII) [Step G]:

18 ml of t-butyl peroxide was slowly added dropwise while 1.9 g (18 mmol) of selenium dioxide was mixed well with 100 ml of dichloromethane at room temperature, followed by stirring at room temperature for 1 hour. The temperature was lowered to 0 ° C. and a solution of 21 g (70 mmol) of 4,17 (20) -Z -pregnadien-3-one of formula (VII) in 100 ml of dichloromethane was slowly added over 10 minutes. After that, the temperature was raised to room temperature and allowed to react for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and extracted with ethyl acetate and distilled water. The organic layer was dried over magnesium sulfate, filtered, and distilled under reduced pressure to obtain 20 g (yield: 91%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.75 (s, 1H), 5.61 (m, 1H), 4.46 (s, 1H), 2.44 to 0.94 (steroid main-body and 1.75 (d, 3H), 1.22 (s, 3H), 0.94 (s, 3H) = 27H)

¹³ C-NMR (75.5 MHz, CDCl ₃ ) δ: 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 18

Preparation of 4,17 (20) -E -prognadien-3-one-16α-ol ( E -gugulsterol) of general formula (VIII) from general formula (VII) [Step G]:

18 ml of t-butylperoxide is slowly added dropwise while 3.9 g (35 mmol) of selenium dioxide is mixed well with 100 ml of dichloromethane at room temperature and stirred at room temperature for 1 hour. The temperature was lowered to 0 ° C. and a solution of 21 g (70 mmol) of 4,17 (20) -Z -pregnadien-3-one of formula (VII) in 100 ml of dichloromethane was slowly added over 10 minutes. After that, the temperature was raised to room temperature and allowed to react for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and extracted with ethyl acetate and distilled water. The organic layer was dried over magnesium sulfate, filtered, and distilled under reduced pressure to obtain 21 g (yield: 93%) of the title compound.

Example 19

Preparation of 4,17 (20) -E -prognadien-3-one-16α-ol ( E -gugulsterol) of general formula (VIII) from general formula (VII) [Step G]:

At a reaction temperature of 0 ° C, 6 g (50 mmol) of N -methylmorpholine- N -oxide was slowly added and stirred for 1 hour while mixing 2 g (18 mmol) of selenium dioxide with 150 ml of dioxane. 9 g (35 mmol) of 4,17 (20) -Z -pregnadien-3-one of the general formula (VII) is slowly added, the temperature is raised to room temperature, and reacted for 2 hours. After completion of the reaction, the solvent was concentrated by distillation under reduced pressure, dissolved in 100 ml of ethyl acetate, washed with brine and distilled water, and the organic layer was distilled under reduced pressure with magnesium sulfate to obtain 22 g of the title compound (yield: 82%). Got it.

Example 20

Preparation of 4,17 (20) -E -prognadiene-3,16-dione of general formula (IV) from general formula (VIII) [Step H]:

At room temperature, 22 g (70 mmol) of E -gugulsterol of the general formula (VIII) are dissolved in 200 ml of dichloromethane, and then 60 g (700 mmol) of activated manganese dioxide are added in one portion and stirred vigorously for 2 hours. After completion of the reaction, manganese dioxide is removed by filtration using a short silica gel column. The solvent was distilled off under reduced pressure to obtain 20.6 g (yield: 94%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.52 (q, 1H), 5.76 (s, 1H), 2.50 to 1.08 (steroid main-body and 1.89 (d, 3H), 1.25 (s, 3H), 1.08 (s, 3H) = 26H)

¹³ C-NMR (75.5 MHz, CDCl 3) δ : 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 21

Preparation of 4,17 (20) -E -prognadiene-3,16-dione of general formula (IV) from general formula (VIII) [Step H]:

At room temperature, 22 g (70 mmol) of E -gugulsterol of the general formula (VIII) are dissolved in 300 ml of dichloromethane, and then 120 g (1.4 mmol) of activated manganese dioxide are added at a time and stirred vigorously for 1 hour. After completion of the reaction, manganese dioxide is removed by filtration using a short silica gel column. The solvent was distilled off under reduced pressure to give 21.4 g (yield: 98%) of the title compound.

According to the present invention, 4,17 (20) -E -prostadiene-3,16-dione ( E -Gugulsteste) represented by the general formula (IV) which effectively lowers low-density lipoprotein and cholesterol levels and raises high-density lipoproteins Ron, and its isomer, 4,17 (20) -Z -prostadiene-3,16-dione ( Z -gugulsterone), represented by the general formula (V), can be effectively and economically synthesized. Therefore, this invention is a useful invention which provides the method which can manufacture the medicine and health food which use the said compound as an active ingredient at low cost with high purity.

Claims (11)

5-Androsten-3β-ol-17-one represented by the following general formula (I) was reacted with ethyltriphenylphosphonium halide in the presence of a strong base to obtain a compound of the general formula (II), followed by C 4,17 (20) -E -prostadiene-3,16-dione of the following general formula (IV) characterized by introducing a hydroxy group at the -16 position to obtain a general formula (III) compound, and oxidizing it E -Gugulsterone).

The method according to claim 1, wherein the anhydrous solvent used is carried out in one or two or more mixed solvents selected from the group consisting of diethyl ether, tetrahydrofuran, dimethyl sulfoxide, benzene, toluene and xylene. The method of claim 1, wherein the strong base is selected from hydrides of alkali metals or alkaline earth metals, lower alkyl metal salts, alkoxides of alkali metals or alkaline earth metals. The method of claim 1 wherein the ethyl triphenyl phosphonium halide is ethyl triphenyl phosphonium chloride ^{_{(Ph 3 P + CH 2 CH}} 3 Cl -), ethyl triphenyl phosphonium bromide ^{_{(Ph 3 P + CH 2 CH}} 3 Br -) And ethyltriphenylphosphonium iodide (Ph ₃ P ⁺ CH ₂ CH ₃ I ⁻ ). The method according to claim 1 or 5, wherein the amount of ethyltriphenylphosphonium halide is 1 to 5 equivalents based on general formula (I). A process for preparing a compound of the general formula (III) from the compound of the general formula (II) according to claim 1, wherein the selenium oxide and the peroxide are reacted in a solvent. The method of claim 6 wherein selenium oxide is selenium dioxide, and the peroxide is hydrogen peroxide (H ₂ O ₂ ), t-butylperoxide (t-BuOOH), N -methylmorpholine N -oxide (NMO) and pyridine N -Oxide (C ₅ H ₅ NO) is one selected from the group consisting of, characterized in that the solvent is an aprotic polar solvent. 4,17 (20) -Z -prostadiene-3,16-dione, which is characterized by photoreaction or thermal reaction or acid catalysis of E -gugulsterone of Formula (IV) prepared in claim 1 (Z-Gugulsterone) Method of Preparation. The method of claim 8, 1 or 2 or more solvents selected from the group consisting of distilled water, methanol, ethanol, acetonitrile, acetone, carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, benzene, toluene and xylene in the isomerization reaction of E -gugulsterone Methylene blue, methylene green, or rose bengal under photoreaction using 0.01 to 0.2 equivalents based on general formula (IV), or In the presence of a solvent of benzene, toluene, xylene or mesitylene, the reaction is thermally reacted at 80 to 200 ° C. for 1 to 48 hours, or P -toluenesulfonic acid to general formula (VI) as an acid catalyst in the presence of one or two or more solvents selected from the group consisting of acetonitrile, acetone, carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, benzene, toluene and xylene A method for producing 4,17 (20) -Z -prostadiene-3,16-dione ( Z -gugulsterone), characterized in that an acid catalyst reaction is carried out at -10 to 160 ° C using -0.5 equivalent. delete delete