KR20040092500A - Process for preparing 4,17(20)-prostadien-3,16-dione from testosterone and the intermediate compounds for preparing the same - Google Patents

Abstract

PURPOSE: A process for preparing 4,17(20)-prostadien-3,16-dione from testosterone and intermediate compounds for preparing the same are provided to lower values for low density lipoprotein and cholesterol and to increase a value for high density lipoprotein. CONSTITUTION: The process for preparing 4,17(20)-E-prostadien-3,16-dione represented by formula VII from testosterone comprises the steps of: reacting testosterone represented by formula I with an alkane diol under a presence of an acid catalyst; reacting with a chrome oxide; reacting with an ethyl triphosphonium halide and a strong base; de-protecting; oxidizing with a selenium compound and a peroxide; and oxidizing it with a manganese oxide.

Description

Method for preparing gugulsterone from testosterone and intermediates for producing the same

The present invention selects the E and Z isomers of 4,17 (20) -prostadiene-3,16-dione (hereinafter referred to as "gugulsterone") using testosterone (I) as a starting material. And a process for preparing 4,17 (20) -E -androsten-3-one-16ol (hereinafter referred to as "gugstersterol") and intermediate composites for the preparation thereof. 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 selective production method and a compound represented by the general formula (IV) and (VI) which is an intermediate for producing the same.

Gugulsterone has been extracted from Indian guggulu trees (Communphora mukul ) and has been used as a traditional antihyperlipidemic drug, and recently it is an effective antagonist of farnesoid orphan receptors (FXR) that are involved in cholesterol metabolism in humans. ( 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 80:20 population gulsterone mixtures with Z to E ratios.

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 may be explosive, which is 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.

Accordingly, an object of the present invention is to obtain gugulsterol and single E form gugulsterone (VII) and Z form gugulsterone (VIII) in high yield, with easy availability and short reaction time from inexpensive starting materials. To provide an economical way to do this.

In view of the above facts, the present inventors have intensively studied, and as shown in the following scheme, they have completed the method of synthesizing gugulsterone from testosterone of general formula (I), which is a useful steroid.

The present invention protects the ketone at the C-3 position with 1,2-ethanediol under test conditions with testosterone as a starting material to obtain a general formula (II) compound, and the hydroxy group at the C-17 position with an oxidizing agent. It was oxidized to give general formula (III). Wittig reaction of ethyltriphenylphosphonium bromide with strong base gave a compound of formula (IV) of carbon-carbon ethyl double bond (C = CH-CH ₃ ). General formula (V) was prepared by deprotecting the ketone protecting group at the C-3 position prior to the introduction of alcohol, and reacted with selenium dioxide (SeO ₂ ) to introduce a hydroxyl group at the C-16 position (VI). Made of gugulsterol. The obtained gugulsterol was reacted with an oxidizing agent to synthesize a single form E -gugulsterone of general formula (VII), from which Z -gugulstere of general formula (VIII) was subjected to photoreaction, thermal reaction, or an acid catalyst. The loan was found to be obtained and the present invention was completed.

That is, this invention provides the method of manufacturing the compound of general formula (II) which protected the ketone of the C-3 position by reaction with 1,2-ethanediol from the compound of general formula (I).

The present invention also provides a method for preparing general formula (III) through an oxidation reaction from a compound of general formula (II).

The present invention also provides a process for preparing the general formula (IV) from the compound of the general formula (III) through a high yield of Wittig reaction.

The present invention also provides a method for preparing a compound of formula (V) through a deprotection reaction from a compound of formula (IV).

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

The present invention also provides a method for preparing a single form E- gurulsterone of general formula (VII) through oxidation from gugulsterol of general formula (VI).

The present invention also provides a process for preparing Z -gugulsterone of general formula (VIII) using a photoreaction, thermal reaction, or acid catalyst from a single E -gugulsterone of general formula (VII). It is.

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

The present invention therefore also provides novel compounds useful as intermediates for preparing gugulsterone in the E and Z form.

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 the compound represented by the general formula (II), the compound represented by the general formula (I) may be reacted with 1,2-ethanediol and an acid catalyst under a solvent.

As the solvent used in this step, solvents such as chloroform, dichloromethane, carbon tetrachloride, tetrahydrofuran, acetonitrile, benzene and toluene are used. Among them, the most preferred solvents are dichloromethane and benzene solvent.

Alkanediols protecting the ketone at the C-3 position are 1,2-ethanediol (ethylene glycol) and 1,3-propanediol, most preferably 1,2-ethanediol.

Acids to be used include borontrifluoro etherate (BF ₃ · Et ₂ O), oxalic acid, and p -toluenesulfonic acid (TsOH), among which p -toluenesulfonic acid is the most preferable acid. The amount of acid used in the reaction is generally 0.01 to 0.2 equivalents based on alkanediol, and most preferably 0.01 to 0.05 equivalents.

The reaction temperature may vary depending on the solvent used, but is usually -10 to 110 ° C, preferably 70 to 100 ° 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 3 hours or less.

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

The compound represented by general formula (III) is a method for producing the compound of general formula (II) by reacting with chromium oxide.

In this process, chromium oxidants such as pyridinium chloro chromate (PCC) and pyridinium dichromate (PDC) are used to oxidize general C-17 secondary alcohol to ketone. Pyridinium chlorochromate (PCC) method is best.

As the solvent used in this step, it is preferable to use dichloromethane as the pyridinium chloro chromate and a solvent such as N and N -dimethylacetamide as the pyridinium dichromate according to the kind of oxidizing agent.

The amount of oxidant to be used varies depending on the oxidizing agent, but usually 1 to 5 equivalents, and most preferably 1.5 to 2.0 equivalents, based on the amount of the general formula (II).

The reaction temperature may vary depending on the oxidizing agent used, but is usually -10 to 30 ° C, preferably -10 to 25 ° C. 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 C] Preparation of a compound represented by general formula (IV).

In order to obtain the compound represented by the general formula (IV), the compound represented by the general formula (III) may be reacted with an ethyltriphenylphosphonium halide and a strong base in anhydrous solvent.

Anhydrous solvents used in this process include a single solvent such as diethyl ether, tetrahydrofuran, hexane, heptane, methanol, ethanol, dimethyl sulfoxide, benzene, toluene, xylene, dimethyl sulfoxide (DMSO) and two or more solvents. Use a mixed solvent containing. Among them, the most preferred solvents are tetrahydrofuran and dimethyl sulfoxide solvent.

Wittig (Wittig) ethyl triphenylphosphonium halide to be used in the reaction include ethyl triphenyl phosphonium chloride ^{_{(Ph 3 P + CH 2 CH}} 3 Cl -), ethyl triphenyl phosphonium bromide (Ph ₃ P ⁺ CH ₂ CH ₃ Br ⁻ ), ethyltriphenylphosphonium iodide (Ph ₃ P ⁺ CH ₂ CH ₃ I ⁻ ), of which ethyltriphenylphosphonium bromide and ethyltriphenylphosphonium iodide are most preferred.

The strong base reagents used include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, organic metal reagents such as n-butyllithium, sec-butyllithium and tert-butyllithium, which are used in general Witig reactions. Alkali metal alcohol base reagents such as methoxide, sodium ethoxide and potassium-t-butoxide are used. Among these, the most preferred bases are sodium hydride and potassium-t-butoxide. The amount of base used for the reaction is generally 1 to 4 equivalents, and preferably 1 to 1.5 equivalents, based on the amount of ethyl triphenylphosphonium bromide forming ylide.

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. Reaction is carried out at -20 degreeC, and the temperature which carries out Wittig reaction with the compound of general formula (III) is synthesize | combined at 25-100 degreeC temperature. Preferably, the solvent is tetrahydrofuran at 50 to 70 ° C, and dimethyl sulfoxide is best at 20 to 80 ° C. 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 D] Preparation of compound represented by general formula (V).

In order to obtain the compound represented by general formula (V), it can obtain by removing a C-3 ketone protecting group from the compound represented by general formula (IV).

Deprotection reaction The solvent used is a mixed solvent in which a single solvent such as distilled water, acetone, chloroform, dichloromethane, acetonitrile, tetrahydrofuran, glacial acetic acid, and two or more solvents are combined. Among them, the most preferred solvent is a mixed solvent of distilled water and acetone.

The deprotecting group reaction reagent used is pyridinium tosylate (PPTS), p-toluenesulfonic acid (TsOH), hydrochloric acid, glacial acetic acid, and the like. Among these, the most preferred deprotecting reagent is pyridinium tosylate (PPTS). . The amount used for the reaction varies depending on the type of reagent, but is usually 0.05 to 0.5 equivalents based on general formula (IV), preferably 0.1 to 0.3 equivalents.

The reaction temperature may vary depending on the solvent and reagent used, but is usually 0 to 100 ° C, preferably 30 to 60 ° C. The reaction time may vary depending on the reaction temperature and the reagent used, but the reaction is usually performed at 30 minutes to 1 day, preferably 3 hours or less.

[Step E] Preparation of Gugul Sterol represented by General Formula (VI).

Gugulsterol represented by the general formula (VI) is a method for producing selenium oxide and a hydrogen peroxide compound by reacting a compound of the general formula (V) in a solvent.

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

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 F] Preparation of Gugulsterone Represented by General Formula (VII)

The gugulsterone represented by the general formula (VII) is obtained by reacting the gugulsterol represented by the general formula (VI) 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 (VI). 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.

[Step G] represented by General Formula (VIII) Z Preparation of Gugulsterone.

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

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

Thus obtained E -gugulsterone of the general formula (VII) and Z -gugulsterone of the general formula (VIII) 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 Cyclo-3- (1,2-ethanediyl Acetal) -5-Androsten-17β-ol of Formula (II) from Formula (I) [Step A]:

In a solution of 28.8 g (100 mmol) of starting material testosterone (I) completely dissolved in 200 ml benzene at room temperature (25 ° C), 6.2 ml (110 mmol) of 1,2-ethanediol and 0.2 g (1 mmol) of p-toluenesulfonic acid Add in order. Heated reflux is performed in the Dean-Stark apparatus and the water removal reaction is performed for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 mL of saturated NaHCO ₃ was added to the reaction mixture, and the benzene layer was extracted. The remaining aqueous layer was further extracted three times with 80 mL of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and distilled under reduced pressure to remove the solvent, and then separated from silica gel to give 25.3 g (yield: 76%) of the title compound.

¹ H NMR (300 MHz, CDCl 3) δ: 5.35 (t, 1H), 3.97 (q, 4H), 3.66 (t, 1H), 2.56 (q, 1H), 2.10 to 0.77 (steroid main-body and 1.06 (s , 3H), 0.78 (s, 3H) = 25H)

¹³ C NMR (75.5 MHz, CDCl 3) δ: 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 2

Preparation of Cyclo-3- (1,2-ethanediyl Acetal) -5-Androsten-17β-ol of Formula (II) from Formula (I) [Step A]:

18.6 mL (330 mmol) of 1,2-ethanediol and 1 g (5 mmol) of p-toluenesulfonic acid in a solution of 28.8 g (100 mmol) of starting material testosterone (I) completely dissolved in 200 mL benzene at room temperature (25 ° C). Add in order. The reflux reaction is performed in a Dean-Stark apparatus for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 mL of saturated NaHCO ₃ was added to the reaction mixture, and the benzene layer was extracted. The remaining aqueous layer was further extracted three times with 80 mL of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and distilled under reduced pressure to remove the solvent, and the mixture was separated from silica gel to obtain 29 g (yield: 87%) of the title compound.

Example 3

Preparation of Cyclo-3- (1,2-ethanediyl Acetal) -5-Androsten-17-one of Formula (III) from Formula (II) [Step B]:

At a reaction temperature of 0 ° C., 28 g (84 mmol) of cyclo-3- (1,2-ethanediyl acetal) -5-androsten-17β-ol of general formula (II) was dissolved in 250 mL of dichloromethane, followed by molecular sieve ( 3 g of molecular sieves 4 ') are added followed by 21.5 g (100 mmol) of pyridinium chlorochromate (PCC). The reaction was carried out for 2 hours while maintaining the temperature, and 200 ml of ethyl ether was 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 23 g (yield: 83%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.29 (s, 1H), 3.87 (s, 1H), 2.48 (d, 1H), 2.26 (q, 1H), 2.04-0.98 (steroid main-body and 0.98 (s, 3H), 0.81 (s, 3H) = 26H)

¹³ C-NMR (75.5 MHz, CDCl ₃ ) δ: 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 4

Preparation of Cyclo-3- (1,2-ethanediyl Acetal) -5-Androsten-17-one of Formula (III) from Formula (II) [Step B]:

At a reaction temperature of 0 ° C., 28 g (84 mmol) of cyclo-3- (1,2-ethanediyl acetal) -5-androsten-17β-ol of the general formula (II) was dissolved in 300 ml of dichloromethane, followed by molecular sieve ( 5 g of molecular sieves 4 ') are added followed by 36 g (168 mmol) of pyridinium chlorochromate (PCC). 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 24.4 g (yield: 88%) of the title compound.

Example 5

Preparation of cyclo-3- (1,2-ethanediyl acetal) -5,17 (20) -Z -androstane of general formula (IV) from general formula (III) [Step C]:

37 g (100 mmol) of ethyltriphenylphosphonium bromide was dissolved in 200 mL of anhydrous tetrahydrofuran at a reaction temperature of 0 ° C, and 110 mL (110 mmol) of potassium t-butoxide (1 mol solution of anhydrous tetrahydrofuran) was added for 15 minutes. Add slowly over. After complete dropwise addition, the reaction mixture was further reacted at room temperature for 30 minutes, followed by 24 g (83.2 mmol) of cyclo-3- (1,2-ethanediyl acetal) -5-androsten-17-one of formula (III). The solution dissolved completely in 150 mL tetrahydrofuran is slowly added at room temperature. The reaction mixture was heated to reflux for 2 hours, and when the reaction was completed, the temperature was lowered to room temperature, the solvent was concentrated in a reduced pressure distillation, and 250 ml of a mixed solution of hexane and ethyl ester (10: 1) was added to the byproduct tree. Phenylphosphinooxide (Ph ₃ P = O) is precipitated and filtered. The organic layer was washed with brine and distilled water, water was removed with magnesium sulfate, filtered and distilled under reduced pressure to obtain 23.1 g (yield: 81%) of the title compound.

¹ H-NMR (300MHz, CDCl ₃ ) δ: 5.38 (t, 1H), 5.16 (q, 1H), 3.97 (m, 4H), 2.57 (q, 1H), 2.23-0.89 (steroid main-body and 1.68 (d, 3H), 1.06 (s, 3H), 0.92 (s, 3H) = 27H)

¹³ C-NMR (75.5 MHz, CDCl ₃ ) δ: 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 6

Preparation of cyclo-3- (1,2-ethanediyl acetal) -5,17 (20) -Z -androstane of general formula (IV) from general formula (III) [Step C]:

40 g (105 mmol) of ethyltriphenylphosphonium bromide are dissolved in 250 mL of anhydrous dimethyl sulfoxide at a reaction temperature of 10 DEG C, and 2.6 g (110 mmol) of sodium hydride are slowly added. After complete addition, the reaction mixture was allowed to react for another 30 minutes at room temperature, followed by 24 g (83.2 mmol) of cyclo-3- (1,2-ethanediyl acetal) -5-androsten-17-one of formula (III). Is added slowly at room temperature. The reaction mixture is further reacted at room temperature for 2 hours, and when the reaction is completed, the reaction mixture is separated into 200 ml of brine and 200 ml of ethyl acetate, and the organic layer is removed with magnesium sulfate. After filtration, the solvent was concentrated in a reduced pressure distillation, and 250 ml of a mixed solution of hexane and ethyl ester (10: 1) was added to precipitate and filter triphenylphosphinooxide (Ph ₃ P = O) as a by-product. Distillation under reduced pressure gave 26.5 g (yield: 93%) of the title compound.

Example 7

Preparation of 4,17 (20) -Z -pragnadien-3-one of general formula (V) from general formula (IV) [Step D]:

26 g (76 mmol) of cyclo-3- (1,2-ethanediyl acetal) -5,17 (20) -Z -androsten of formula (IV) was dissolved in 200 ml of a 5% acetone mixed solution of distilled water and pyridinium. 1.8 g (7 mmol) of tosylate (PPTS) are added. The reaction mixture is heated to 40 ° C. for 2 hours. After completion of the reaction, acetone was removed by distillation under reduced pressure and extracted with 100 mL of distilled water and 150 mL of ethyl acetate. Water was removed from the organic layer with magnesium sulfate, filtered, and distilled under reduced pressure to obtain 21.3 g (yield: 94%) 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 (m, 19H), 1.71 (d, 3H), 1.23 (s, 3H), 0.93 (s, 3H)

¹³C NMR (75.5 MHz, CDCl3) 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 8

Preparation of 4,17 (20) -Z -pragnadien-3-one of general formula (V) from general formula (IV) [Step D]:

5 g (15 mmol) of cyclo-3- (1,2-ethanediyl acetal) -5,17 (20) -Z -androsten of formula (IV) were mixed with 45 ml of 75% glacial acetic acid prepared in advance and Heated to 60 ° C. for 30 minutes. After completion of the reaction, the temperature was lowered to room temperature and extracted with brine (30 mL) and ethyl acetate (50 mL x 3). The glacial acetic acid remaining in the organic layer was washed again with saturated NaHCO ₃ and distilled water, dried with magnesium sulfate, filtered, and distilled under reduced pressure to obtain 3.8 g (yield: 84%) of the title compound.

Example 9

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

18 ml of t-butylperoxide is slowly added dropwise while 1.9 g (18 mmol) of selenium dioxide is 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 (V) 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 10

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

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 (V) 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 11

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

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 (V) was slowly added, and the temperature was raised to room temperature, followed by reaction 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 12

Preparation of 4,17 (20) -E -prognadiene-3,16-dione ( E -gugulsterone) of general formula (VII) from general formula (VI) [Step F]:

At room temperature, 22 g (70 mmol) of E -gugulsterol of formula (VI) 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)

¹³C NMR (75.5 MHz, CDCl3) 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 13

Preparation of 4,17 (20) -E -prognadiene-3,16-dione ( E -gugulsterone) of general formula (VII) from general formula (VI) [Step F]:

At room temperature, 22 g (70 mmol) of E -gugulsterol of formula (VI) are dissolved in 300 ml of dichloromethane, and then 120 g (1.4 mol) of activated manganese dioxide are added in one portion 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.

Example 14

Preparation of 4,17 (20) -Z -prognadiene-3,16-dione ( Z -gugulsterone) of general formula (VIII) from general formula (VII) [Step G]:

At room temperature, 1 g (3.2 mmol) of E -gugulsterone of general formula (VII) are 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 15

Preparation of 4,17 (20) -Z -prognadiene-3,16-dione ( Z -gugulsterone) of general formula (VIII) from general formula (VII) [Step G]:

At room temperature, 1 g (3.2 mmol) of E -gugulsterone of general formula (VII) are dissolved in 40 ml of toluene, and the container is filled with nitrogen and completely closed. 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 16

Preparation of 4,17 (20) -Z -prognadiene-3,16-dione ( Z -gugulsterone) of general formula (VIII) from general formula (VII) [Step G]:

At room temperature, 1 g (3.2 mmol) of E -gugulsterone (100) 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.

According to the present invention, 4,17 (20) -E -prostadie-3 represented by the general formula (VII), which effectively lowers low-density lipoprotein and cholesterol levels by using inexpensive testosterone as a starting material, and raises high-density lipoprotein, 16-dione (E -Guggulsterone; E - gugul Ste Ron) and 4,17 (20) represented by its isomer of formula (VIII) - Z - prostasin diene -3,16- dione (Z -Guggulsterone; Z Gugulsterone) can be synthesized effectively and economically. 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 (8)

After reacting testosterone of the general formula (I) with an alkanediol in the presence of an acid catalyst to obtain a general formula (II) compound, and then reacting it with chromium oxide to obtain a general formula (III) compound, to which ethyltriphenylphosphate was added. Reaction of the phosphium halide with a strong base gives a compound of formula (IV), deprotection of the resulting compound to give a compound of formula (V), and then oxidation with selenium oxide and a peroxide to yield a compound of formula (VI), and manganese oxide A process for preparing 4,17 (20) -E -prostadiene-3,16-dione of general formula (VII), characterized in that it is oxidized. 2. The process of claim 1 wherein the acid catalyst is Lewis acid and the alkanediol is 1,2-ethanediol or 1,3-propanediol. The method according to claim 1, wherein the deprotection reaction is performed in one or two or more mixed reagents selected from the group consisting of pyridinium tosylate (PPTS), p -toluenesulfonic acid (TsOH), hydrochloric acid and glacial acetic acid. The method of claim 1 wherein the chromium oxide is pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC). 4,17 (20), characterized in a prostasin diene -3,16- dione back Sikkim photoreaction, thermal reaction or acid catalyzed reaction-4,17 claim 20 of the base 1-E Z-prostasin Process for preparing diene-3,16-dione. The method of claim 5, wherein the photoreaction is performed using methylene blue, methylene green or rose bengal as a photocatalyst. The method of claim 5 wherein the thermal reaction is heated to reflux for 1 to 48 hours at 80 to 200 ° C. in a benzene, toluene, xylene, mesitylene solvent. 6. The process of claim 5, wherein the acid catalysis is carried out using p -toluenesulfonic acid.