KR100639655B1 - Process for preparing 4,1720-prostadien-3,16-dione from 16?,17?-epoxypregnenolone and the intermediate compounds for preparing the same - Google Patents

Abstract

The present invention is a general formula known to effectively lower human low density lipoprotein (LDL) and cholesterol levels from 16α, 17α-epoxypregnenolone (I) and increase high density lipoprotein (HDL). A method of selectively preparing only 4,17 (20) -E -prostadiene-3,16-dione represented by (III) is provided.

Description

Process for preparing 4,17 (20) -prostadiene-3,16-dione from 16α, 17α-epoxypregnenolone and intermediates for producing the same {PROCESS FOR PREPARING 4,17 (20) -PROSTADIEN-3,16 -DIONE FROM 16α, 17α-EPOXYPREGNENOLONE AND THE INTERMEDIATE COMPOUNDS FOR PREPARING THE SAME}

The present invention utilizes 16α, 17α-epoxypregnenolone (I) as a starting material for 4,17 (20) -prostadiene-3,16-dione (Guggulsterone). A method for the selective preparation of E- and Z- isomers and intermediate composites for the preparation thereof. More specifically, the present invention effectively reduces the low density lipoprotein (LDL) and cholesterol levels that cause human hyperlipidemia, and the selective preparation of E -Gugulsterone which raises the high density lipoprotein (HDL). A 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). Existing route for treatment or study using gugulsterone was used from natural guggullu extract or 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.

Compound (5) in the method described in patent publication EP 0 447 706 A1 has the following drawbacks in the method of synthesis compared to its effectiveness:

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 methods described in this document cannot be repeated, and it is not a method that can easily and economically prepare Z or E single gugulsterone. Has been required.

It is an object of the present invention to provide economical production of gugulsterol and single E form of gugulsterone (III) in high yields, in a short reaction time, from readily available and inexpensive 16α, 17α-epoxypregnenolone starting materials. Is to provide a way.

In view of the above facts, the present inventors have intensively studied, and as shown in the following reaction scheme, they have completed the method of synthesizing gugulsterone from 16α, 17α-epoxypregnenolone of general formula (I), which is a useful steroid.

(Scheme)

The present invention reacts 16α, 17α-epoxypregnenolone [16α, 17α-Epoxypregnenolone (I)] with hydrazine (NH ₂ NH ₂ ) as a starting material to synthesize general formula (II) in a single process, and separate it The present invention was completed by oxidizing aluminum isopropoxide without purification to obtain a single form E -gugulsterone of general formula (III).

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 single E -gugulsterone of general formula (III) through a single oxidation reaction from a compound of general formula (II).

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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 the general formula (II) is reacted with a base and hydrazine (NH ₂ NH ₂ ) at a high temperature from the compound represented by the general formula (I) to obtain a single reaction.

The hydrazine used in this process uses monohydrate or anhydride, most suitably monohydrate hydrazine. The amount of hydrazine used in the reaction is generally 1 to 40 equivalents based on general formula (I), and most preferably 1.5 to 2.5 equivalents in the case of organometallic reagents depending on the reaction conditions of the base used. In the case of hydroxide, it is best to use 10 to 20 equivalents.

The solvent used in this step is methanol, ethanol, butanol, ethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile dimethyl sulfoxide, benzene, toluene, xylene, diethylene glycol dimethyl ether, diethylene glycol monomethyl A single solvent or a mixed solvent of two solvents such as ether and diethylene glycol is used. Of these, the most preferred solvents are tetrahydrofuran and diethylene glycol.

Bases to be used include alkali metal hydroxides such as triethylamine, sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, n-butyllithium, sec-butyllithium and tert Organometallic reagents such as butyllithium, lithium diisopropylamide (LDA) and potassium diisopropylamide (KDA), and alkali metal alcohol base reagents such as sodium methoxide, sodium ethoxide and potassium-t-butoxide use. Among them, the most preferred bases are sodium hydroxide, potassium hydroxide and triethylamine. The amount of base used for the reaction is 3 to 5 equivalents of triethylamine, 2 to 15 equivalents for alkali metal hydroxide, and 1 to 3 equivalents for alkali metal hydride, depending on the type of base. It is preferable to use 1 to 3 equivalents in the case of the organometallic reagent and 1 to 4 equivalents in the case of the alkali metal alcohol base.

The reaction temperature may vary depending on the base and solvent used, but is usually -100 to 190 ° C. Preferably, triethylamine is 0 to 30 ° C. Alkali metal hydrides and organometallic reagents are -100 to -78 ° C. The alkali metal alcohol base is 20 to 100 deg. C, and the alkali metal hydroxide is most preferably 80 to 160 deg. The reaction time may vary depending on the reaction temperature, the base used, and the solvent, but the reaction is generally performed at 30 minutes to 48 hours, preferably 4 hours or less.

[Step B] Preparation of E -gugulsterone represented by General Formula (III).

Gugulsterone represented by formula (III) is obtained by the Oppenauer oxidation reaction using a compound represented by formula (II) 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, with aluminum isopropoxide being most preferred. The best. The amount of aluminum oxidant to be used is generally 0.3 to 1.5 equivalents based on General Formula (II), 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, cyclonucleic acid temperature and cycloheptanone are used as ketones used as reducing agents 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.

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E -gugulsterone, the general formula (III) obtained in this way, 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 5,17 (20) -Z -prognadiene-3β, 16α-diol of general formula (II) from general formula (I) [Step A]:

At room temperature, 33.1 g (100 mmol) of 16α, 17α-epoxypregnenolone (I) and 50 g of potassium hydroxide were dissolved in 200 ml of diethylene glycol, and 97 ml (2 mol) of hydrazine monohydrate having a purity of 98%. Add. The temperature of the reactant is raised to 120 ° C. and heated to reflux for 1 hour, the solvent cooler is removed again, and the reaction is performed at 160 ° C. for 2 hours. Confirm termination of the reaction by TLC and lower the temperature to room temperature. The reaction was mixed with 200 ml of distilled water and extracted three times with 200 ml of chloroform. The organic layer was dried over magnesium sulfate and filtered to completely remove the residual solvent in high vacuum to give 28.8 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, 32.0, 31.2, 21.5, 19.7 , 17.7, 13.6

Example 2

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

At 0 ° C., 33.1 g (100 mmol) of 16α, 17α-epoxypregnenolone of formula (I) and 7.9 mL (250 mmol) of 98% pure anhydrous hydrazine are dissolved in 200 mL of anhydrous tetrahydrofuran. After 2 hours, 50 ml of triethylamine was added at the same temperature, and the temperature was raised to room temperature and allowed to react for 10 hours. The reaction is terminated by TLC and the solvent is removed completely under reduced pressure distillation. The organic layer was extracted using 200 ml of distilled water and 200 ml of chloroform, and the organic layer was dried over magnesium sulfate and filtered to obtain 20.3 g (yield: 64%) of the title compound.

Example 3

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

At room temperature, 25 g (79 mmol) of 5,17 (20) -E -pregnadiene-3β, 16α-diol of general formula (II) was dissolved in 200 ml of benzene, 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 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 4

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

At room temperature, 25 g (79 mmol) of 5,17 (20) -E -pregnadiene-3β, 16α-diol, which is general formula (II), 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 mixture) of the title compound.

Example 5

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

Of 5,17 (20) Formula (Ⅱ) at room temperature - E - Pre the Nadi yen -3β, 16α- diol 25 g (79 mmol) dissolved in toluene after a 200 ㎖, cyclohexanone 82 ㎖ 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 6

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

At room temperature, 8.3 g (26 mmol) of general formula (II) 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.

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According to the present invention, 4,17 (20) -E -prostadiene-3,16-dione ( E -Guggulsterone) represented by the general formula (III), which effectively lowers low-density lipoprotein and cholesterol levels and raises high-density lipoprotein; E -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 (10)

delete delete delete delete 4,17 (20) of general formula (III) characterized by reacting 16α, 17α-epoxypregnenolone of general formula (I) with hydrazine and a base to give a compound of general formula (II) ) -E -Prostadiene-3,16-dione ( E -Gugulsterone; E- Guggulsterone) method of preparation. The method of claim 5, The base is triethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium hydride, sodium hydride, potassium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide (LDA), potassium 4,17 (20) -E -prostar of general formula (III), characterized in that it is one kind selected from diisopropylamide (KDA), sodium methoxide, sodium ethoxide and potassium-t-butoxide. the method of; - (E -Guggulsterone gugul Ste Ron E) diene -3,16- Dion. The method of claim 6, The base is 4,17 (20) -E-prostadiene-3,16-dione (E-gugulsterone; E-) of formula (III), characterized in that sodium hydroxide, potassium hydroxide or triethylamine. Guggulsterone). The method of claim 5, 4,17 (20) -E -prostadiene-3 of formula (III), characterized in that 1 to 40 equivalents of hydrazine are reacted with 16α, 17α-epoxypregnenolone of formula (I), the method of; - (E -Guggulsterone gugul Ste Ron E) 16- Dion. The method of claim 5, Preparation of; - (E -Guggulsterone gugul Ste Ron E) 4,17 (20) represented by the general formula (III), characterized in the use of aluminum alkoxides in the oxidation reaction - - E prostasin diene -3,16- dione Way. The method of claim 5, The solvent used for the oxidation reaction is benzene, toluene, xylene, mesitylene, 4,17 (20) -E -prostadiene-3,16-dione ( E -gugulsterone) of formula (III). E- Guggulsterone).