KR20040092518A - Process for preparing 4,17(20)-prostadien-3,16-dione from progesterone and the intermediate compounds for preparing the same - Google Patents

Abstract

PURPOSE: A process for preparing 4,17(20)-prostadien-3,16-dione from progesterone 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)-prostadien-3,16-dione represented by formula VII from progesterone comprises the steps of: reducing the progesterone represented by formula I; oxidizing with a manganese dioxide; reacting with a methane sulfonyl chloride or p-toluene sulfonyl chloride; olefinating by treating the obtained compound with a strong base; selective oxidizing with a selenium compound and a peroxide; and oxidizing it.

Description

Method for preparing gugulsterone from progesterone and intermediates for producing the same {PROCESS FOR PREPARING 4,17 (20) -PROSTADIEN-3,16-DIONE FROM PROGESTERONE AND THE INTERMEDIATE COMPOUNDS FOR PREPARING THE SAME}

The present invention provides a method for preparing 4,17 (20) -prostadiene-3,16-dione (Guggulsterone; hereinafter referred to as "gugulsterone") using progesterone (I) as a starting material and 4,17 ( 20) -Androsten-3-one-16-ol (Guggulsterol; hereinafter referred to as "gugulsterol") and an intermediate composite for producing the same. More specifically, the present invention provides a method for preparing gugulsterone that effectively lowers low density lipoprotein (LDL) and cholesterol levels that cause human hyperlipidemia and increases high density lipoprotein (HDL). It relates to an intermediate for manufacturing.

Gugulsterone has been extracted from Indian guggulu trees (Commyphora mukul ) and has been used as a traditional antihyperlipidemic drug, and recently it is an effective antagonist of farnesoid orphan receptors (FXRs) 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 the mixture (3) with potassium hydroxide in methanol to give 5,17 (20) -trans-prignadiene-3β, 16β and 3β, 16α-diol (4) in the form of a mixture, which is aluminum isobutoxide or aluminum Oxidation with phenoxide discloses the synthesis of a gugulsterone mixture with a Z: and E- form 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 may be explosive, which is dangerous for general industrial processes.

3) The acetic acid solvent used in the second reaction step (ii) has 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 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 document cannot be repeated, and since it is not a method for easily and economically producing gugulsterone, the emergence of a method that is more reliable than such a method has been urgently required.

It is an object of the present invention to provide an economical process for the production of gugulsterol (VI) and gugulsterone (VII) in high yields in a short reaction time from readily available and inexpensive starting materials of progesterone.

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 progesterone of general formula (I), which is a useful steroid.

The present invention makes alcohol compounds of the general formula (II) using progesterone as a starting material and ketones at the C-3 and C-20 positions using a general reducing agent, and again using a selective oxidizing agent at the C-3 position. Only alcohols were oxidized to form ketone compounds of formula (III). A p -toluenesulfonyl group or a methanesulfonyl group was introduced to the remaining C-20 alcohol as a good leaving group to prepare a compound of formula (IV), and then reacted with a base to obtain a general formula (V). The general formula (V) compound thus synthesized is obtained in a mixed state of the E- and Z-isomers. This was reacted with selenium dioxide (SeO ₂ ) without a separate separation process to introduce a hydroxyl group at the C-16 position to make a gugul sterol of formula (VI). Finally, it was found that the reaction of gugulsterol of general formula (VI) with an oxidizing agent yielded a gugulsterone mixture of general formula (VII), thus completing the present invention.

That is, this invention provides the method of manufacturing a compound of general formula (II) from a compound of general formula (I) using a conventional reducing agent.

The present invention also provides a method for preparing a ketone compound of the general formula (III) by using a selective oxidizing agent as a catalyst from the general formula (II) compound.

The present invention also provides a method for preparing a compound of formula (IV) by introducing a good leaving group by reacting p -toluenesulfonylchloride or methanesulfonyl chloride with a base from a compound of formula (III).

The present invention also provides a method for preparing the mixture of the E- and Z- isomers of the general formula (V) through an olefination reaction using an inorganic or organic salt from the compound of the general formula (IV).

The present invention also provides a process for preparing E- and Z- gugulsterol mixtures of formula (VI) using selective oxidants from compounds of formula (V).

In addition, the present invention is to provide a process for preparing E- and Z- gugul Ste Rhone mixture of the general formula (VII) through an oxidation reaction from E- and Z- gugul sterol mixtures of general formula (VI).

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).

The compound represented by general formula (II) can be obtained through the reaction using a reducing agent from the compound of general formula (I).

Examples of the solvent used in this step include methanol, ethanol, diethyl ether, tetrahydrofuran, dichloromethane, and the like, and methanol and ethanol are more preferable.

Reducing agents used in ketone reduction reactions include aluminum hydride reducing agents such as lithium aluminum hydride (LAH), diisobutylaluminum hydride (DIBAL-H), sodium hydrogen borohydride (NaBH ₄ ), and lithium borohydride (LiBH ₄ ). Reduction reactions using boron hydride reducing agents. Among them, a reaction using a boron hydride reducing agent is suitable, and the most preferred is sodium hydrogen borohydride (NaBH ₄ ). The amount of reducing agent to be used is generally 0.5 to 4 equivalents relative to General Formula (I), and preferably 1.5 to 2.5 equivalents is the best.

The reaction temperature may vary depending on the solvent and reducing agent used, but is usually -100 to 60 ° C, preferably at -78 ° C to 25 ° C. The reaction time may vary depending on the reaction temperature and the solvent used, but the reaction is usually performed at 30 minutes to 6 hours, preferably 2 hours or less.

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

The compound represented by general formula (III) is obtained by reacting a selective oxidizing agent with the general formula (II) compound.

In this process, the oxidizing agent that selectively oxidizes only olefinic hydroxy to form a ketone is activated manganese dioxide (MnO ₂ ). The amount of the oxidant to be used is usually 1 to 40 equivalents based on the amount of the general formula (II) compound, most preferably 10 to 20 equivalents.

Solvents used in this process include pentane, hexane, heptane, petroleum ether, benzene, toluene, xylene, acetone, chloroform, dichloromethane, carbon tetrachloride, and the most preferred solvent is dichloromethane.

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 catalyst equivalent used, but is usually carried out at 30 minutes to 12 hours, preferably 2 hours or less.

[Step C] Preparation of a compound represented by general formula (IV).

The compound represented by the general formula (IV) is obtained by reacting the compound represented by the general formula (III) with p -toluenesulfonyl chloride or methanesulfonyl chloride in the presence of a base.

The reagent used in this process is p -toluenesulfonyl chloride or methanesulfonyl chloride, and the amount used is usually 1 to 4 equivalents to compound (III), most preferably 2 to 3 equivalents This is the best.

Solvents used are N , N -dimethylformamide (DMF), N , N -dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, acetone, ethyl acetate, tetrahydrofuran, carbon tetrachloride, chloroform, dichloromethane, benzene , Toluene, pyridine and the like. Among them, most preferred are dichloromethane and pyridine.

Examples of the base used may include amine bases such as pyridine, triethylamine, imidazole, N , and N -dimethylaminopyridine. Most preferred among these are pyridine, N , N -dimethylaminopyridine. The amount of base to be used is usually 1 to 4 equivalents to general formula (III), and most preferably 1.5 to 2.5 equivalents.

The reaction temperature may vary depending on the solvent used, but is usually -10 to 40 ° C, preferably at 0 ° C to 25 ° C. The reaction time may vary depending on the reaction temperature and the solvent used, but the reaction is generally performed at 1 hour to 1 day, preferably 5 hours or less.

[Step D] Preparation of compound represented by general formula (V).

The compound represented by the general formula (V) is obtained by treating the compound represented by the general formula (IV) with a strong base to olefin it.

Base reagents used in this process include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal alcohol base reagents such as sodium methoxide, sodium ethoxide and potassium-t-butoxide, pyridine and 1,5- Amine salts of diazabicyclo [4,3,0] non-5-ene (DBN), 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) are used. The most preferred of these is sodium methoxide, pyridine. The amount of base used in the reaction varies depending on the base used, but in general, alkali metal hydride, alkali metal alcohol base and amine salt are used in an amount of 1 to 4 equivalents based on general formula (IV), and pyridine is used as a solvent. Good to do.

Solvents used include N , N -dimethylformamide (DMF), N , N -dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, methanol, ethanol, butanol, tetrahydrofuran, carbon tetrachloride, chloroform, dichloromethane, Benzene, toluene, pyridine and the like. Among these, most preferred are dimethyl sulfoxide, methanol and pyridine.

The reaction temperature may vary depending on the type of solvent and base used, but is usually -78 to 150 ° C, preferably at 25 to 120 ° C. The reaction time may vary depending on the reaction temperature and the base used, but is usually carried out at 1 hour to 1 day, preferably 5 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.

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. 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 ethers 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.

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

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

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 a 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.

Gugulsterone of the general formula (VII) thus obtained is a substance 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 4-progene-3,20-diol of formula (II) from compound of formula (I) [Step A]:

At a reaction temperature of 0 ° C., 31.5 g (100 mmol) of progesterone of formula (I) are dissolved in 300 mL of methanol, and 7.6 g (200 mmol) of sodium hydrogen boride (NaBH ₄ ) are added very carefully. After reacting for 2 hours at a temperature of 20 ° C, the solvent is distilled off under reduced pressure. Extraction with ethyl acetate and brine removes the organic layer with magnesium sulfate. Filtration and distillation of the solvent under reduced pressure yielded 31.2 g (yield: 98%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.30 (s, 1H), 4.16 (s, 1H), 3.74 (d, 1H), 2.22 to 0.77 (steroid main-body and 1.15 (d, 3H), 1.08 (s, 3H), 0.80 (s, 3H) = 29H)

¹³ C-NMR (75.5 MHz, CDCl 3) δ : 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 2

Preparation of 4-progene-3,20-diol of formula (II) from compound of formula (I) [Step A]:

Dissolve 31.5 g (100 mmol) of progesterone of formula (I) in 300 ml of anhydrous dichloromethane at reaction temperature -78 ° C, and 220 ml of diisobutylaluminum hydride (DIBAL-H) (1.0 M hexane solution) very carefully. Add. After the reaction was carried out at the same temperature for 2 hours, the temperature was raised to -20 ° C and 5 ml of ethyl acetate was added for further reaction for 20 minutes. The temperature is raised to 0 ° C. and 1 ml of distilled water is slowly added to remove all reducing agents. 10% aqueous sulfuric acid solution was added to extract the organic layer, and the organic layer was washed again with distilled water, followed by removal of water with magnesium sulfate. Filtration and distillation of the solvent under reduced pressure yielded 30.6 g (yield: 96%) of the title compound.

Example 3

Preparation of 20-hydro-4-progenen-3-one of formula (III) from compound of formula (II) [Step B]:

At room temperature, 30 g (94 mmol) of 4-progene-3,20-diol of formula (II) was dissolved in 300 ml of dichloromethane, and then 81 g (940 mmol) of activated manganese dioxide was added at a time and the temperature was raised to 40 ° C. Raise and stir vigorously for 2 hours. After completion of the reaction, manganese dioxide is removed by passing through a short silica gel column. The solvent was distilled off under reduced pressure to give 27.4 g (yield: 92%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.74 (s, 1H), 3.74 (d, 1H), 2.40-0.79 (steroid main-body and 1.20 (s, 3H), 1.15 (d, 3H), 0.82 (s, 3H) = 30H)

¹³ C-NMR (75.5 MHz, CDCl 3) δ : 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 4

Preparation of 20-hydro-4-progenen-3-one of formula (III) from compound of formula (II) [Step B]:

At room temperature, 30 g (94 mmol) of 4-progene-3,20-diol of formula (II) was dissolved in 300 ml of dichloromethane, and then 163 g (1.88 mmol) of activated manganese dioxide were added at a time, and the temperature was raised to 40 ° C. Stir vigorously for hours. After completion of the reaction, manganese dioxide is removed by passing through a short silica gel column. The solvent was distilled off under reduced pressure to give 28.6 g (yield: 96%) of the title compound.

Example 5

Preparation of 20- ( p -toluenesulfonyl) -4-progenen-3-one of general formula (IV) from general formula (III) [Step C]:

28 g (88.5 mmol) of 20-hydroxy-4-progenen-3-one of formula (III) and 21.6 g (177 mmol) of N , N -dimethylaminopyridine (DMAP) at reaction temperature of 0 ° C Dissolve in 350 ml of methane and slowly add 25.3 g (133 mmol) of p -toluenesulfonylchloride (TsCl). The temperature is raised to room temperature and the reaction is allowed to proceed for 4 hours. The reaction was terminated by TLC, and 150 ml of an aqueous ammonium chloride (NH ₄ Cl) solution was added thereto to extract the organic layer, followed by removal of water with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 35.8 g (yield: 86%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.79 (d, 2H), 7.32 (d, 2H), 5.74 (s, 1H), 4.15 (d, 1H), 2.45 to 0.80 (steroid main-body and 1.15 (s, 3H), 0.83 (s, 3H) = 32H)

¹³ C-NMR (75.5 MHz, CDCl 3) δ : 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 6

Preparation of 20- (methanesulfonyl) -4-progenen-3-one of formula (IV) from formula (III) [Step C]:

28 g (88.5 mmol) of 20-hydroxy-4-progenen-3-one of formula (III) and 17 mL (124 mmol) of triethylamine (TEA) were added to 250 mL of anhydrous dichloromethane at a reaction temperature of 0 ° C. Dissolve and slowly add 8.2 mL (106 mmol) of methanesulfonylchloride (MsCl). The temperature is raised to room temperature and the reaction is allowed to proceed for 4 hours. The reaction was terminated by TLC, and 100 ml of an aqueous ammonium chloride (NH ₄ Cl) solution was added to extract the organic layer, followed by removal of water with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 33.2 g (yield: 95%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.74 (s, 1H), 4.12 (d, 1H), 3.07 (s, 3H), 2.45 to 0.80 (steroid main-body and 1.18 (s, 3H), 1.03 (d, 3H), 0.95 (s, 3H) = 29H)

¹³ C-NMR (75.5 MHz, CDCl 3) δ : 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 7

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

At room temperature 35 g (74 mmol) of 20- ( p -toluenesulfonyl) -4-progenen-3-one of formula (IV) are dissolved in 100 ml of pyridine. The temperature of the reaction is raised to 120 ° C. and refluxed for 3 hours. After completion of the reaction remove the pyridine solvent was removed under reduced pressure and 50 ℃, 1 N melt the remaining reaction product in ethyl acetate to 150 ㎖ - and wash with hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 21.4 g (yield: 97%) 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 8

Preparation of 4,17 (20) -pragnadien-3-one E , Z -mixture of Formula (V) from Compound (IV) [Step D]:

At room temperature, 17.5 g (37 mmol) of 20- ( p -toluenesulfonyl) -4-progenen-3-one of general formula (IV) is dissolved in 80 ml of anhydrous methanol. 6 g (111 mmol) of sodium methoxide are added and the reaction is heated to reflux for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, and the remaining reactant was dissolved in 100 ml of ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 10.1 g (yield: 91%) of the title compound.

Example 9

Preparation of 4,17 (20) -pragnadien-3-one E , Z -mixture of Formula (V) from Compound (IV) [Step D]:

At room temperature, 20 g (51 mmol) of 20- (methanesulfonyl) -4-progenen-3-one of formula IV are dissolved in 80 ml of pyridine. The temperature of the reaction is raised to 120 ° C. and refluxed for 2 hours. After completion of the reaction remove the pyridine solvent was removed under reduced pressure and 50 ℃, 1 N melt the remaining reaction product in 100 ㎖ ethyl acetate- and wash with hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 14.5 g (yield: 95%) of the title compound.

Example 10

The pre-Nadi en-3-one E, Z - - Formula (IV) Formula (V) 4,17 (20) from the compound mixture of E, Z -mixture) Preparation of D]:

At room temperature, 10 g (25.5 mmol) of 20- (methanesulfonyl) -4-progenen-3-one of formula (IV) are dissolved in 80 ml of anhydrous methanol. 5.5 g (102 mmol) of sodium methoxide are added and the reaction is allowed to reflux for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, and the remaining reactant was dissolved in 100 ml of ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 7.1 g (yield: 93%) of the title compound.

Example 11

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

18 ml of t-butylperoxide is slowly added to 1.9 g (18 mmol) of selenium dioxide in 100 ml of dichloromethane at room temperature, followed by stirring at room temperature for 1 hour. After the temperature was lowered to 0 ° C., a solution of 21 g (70 mmol) of 4,17 (20) -pregnadien-3-one of formula (V) in 100 ml of dichloromethane was slowly added over 10 minutes. The temperature is 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.

Example 12

Preparation of 4,17 (20) -pregnadien-3-one-16-ol (gugul sterol) of general formula (VI) from compound of 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. After the temperature was lowered to 0 ° C., a solution of 21 g (70 mmol) of 4,17 (20) -pregnadien-3-one of formula (V) in 100 ml of dichloromethane was slowly added over 10 minutes. The temperature is 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 13

Preparation of 4,17 (20) -prognadien-3-one-16-ol (gugulsterol) of the general formula (VI) from the compound of the 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) -pregnadien-3-one of the general formula (V) was slowly added, and the temperature was raised to room temperature and allowed to react 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 14

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

22 g (70 mmol) of gugulsterol of formula (VI) are dissolved in 200 mL of dichloromethane at room temperature, and then 60 g (700 mmol) of activated manganese dioxide are added at once and vigorously stirred 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.

Example 15

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

At room temperature, 22 g (70 mmol) of gugulsterol of formula (VI) are dissolved in 300 ml of dichloromethane, and then 120 g (1.4 mmol) 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.

According to the present invention, 4,17 (20) -prostadiene-3,16-dione (gugulsterone) represented by the general formula (VII), which effectively lowers low-density lipoprotein and cholesterol levels and raises high-density lipoprotein, is effective. It can be synthesized both economically 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 (4)

After reducing the progesterone of the general formula (I) to obtain a general formula (II) compound, it is oxidized with manganese dioxide to obtain a general formula (III) compound, to which methanesulfonyl chloride or p -toluenesulfonyl chloride is added. Reacting to obtain a compound of formula (IV), and treating the resulting compound with a strong base to olefin to obtain a compound of formula (V), which is subjected to selective oxidation with selenium oxide and peroxide, To obtain 17 (20) -prostadien-3-one-16-ol and oxidize it to 4,17 (20) -prostadiene-3,16-dione of formula (VII) characterized by Manufacturing method. 2. The reduction reaction according to claim 1, wherein the reduction reaction is carried out using an aluminum hydride reducing agent such as lithium aluminum hydride (LAH), diisobutyl aluminum hydride (DIBAL-H), sodium hydrogen borohydride (NaBH ₄ ), lithium borohydride (LiBH ₄ ), or the like. Reduction reaction using a boron hydride reducing agent. The method according to claim 1, wherein the selective oxidation reaction uses selenium dioxide and a peroxide. The method according to claim 1, wherein the oxidation reaction is carried out in one or more selected from the group consisting of pyridinium chlorochromate, pyridinium dichromate and activated manganese dioxide (MnO ₂ ).