CN1795201A

CN1795201A - Process for preparing guggulsterones and guggulsterol

Info

Publication number: CN1795201A
Application number: CNA200480014290XA
Authority: CN
Inventors: 姜宪中; 咸政烨; 陈政郁
Original assignee: Individual
Current assignee: Hundai Motro Company seoul National University Industry Foundation
Priority date: 2003-04-24
Filing date: 2004-04-24
Publication date: 2006-06-28
Anticipated expiration: 2024-04-24
Also published as: KR20040092066A; KR100639655B1; CN100352830C

Abstract

The present invention relates to a method for selective preparing 4,17 (20)-E-pregnadiene-3,16-dione (E-guggul-sterone) of the formula (III) and 4,17 (20)-Z-pregnadiene-3,16-dione (Z-guggulsterone) of the formula (IV) having an effect of lowering the elevated low density lipoprotein (LDL) and high levels of the cholesterol effectively, and elevating the low levels of the high density lipoprotein (HDL) from a easy-available steroid of the following formula (I). Also, the present invention provides a method for preparation of the compound of the above formula (II).

Description

The preparation method of myrrh sterone and guggulusterol

Technical field

The present invention relates to 4,17 (20)-pregnant diene-3, the preparation method of 16-diketone (calling " myrrh sterone " in the following text), prepare the preparation method of compound of the intermediate formula (II) of the method for Z-type myrrh sterone isomer and compound (III) by E-type myrrh sterone, the effect of myrrh sterone is that high-caliber low-density lipoprotein (LDL) and high-caliber cholesterol are reduced effectively, and low-level high-density lipoprotein (HDL) (HDL) is raise.

Background technology

From commiphora mukul tree (vegetable formal name: extracted the myrrh sterone Commiphora mukul), and treat hyperlipidaemia with it traditionally, known it still be effective antagonist (Nature of the metabolic Farnesoid orphan receptor of cholesterol regulating (FXR), 2002, June, 411.; Science, 2002, May, 1703).Past, adopted the myrrh sterone of E-type or Z-type to be used as hypolipidemic, the acquisition mode of this myrrh sterone is to extract the resin that guggal resin is set, necessity, the further purification of works such as employing HPLC (high performance liquid chromatography).EP 0 447 706 A1 disclose a kind of method of synthetic myrrh sterone mixture.Be shown below, with the ketone group and the acetate groups of lithium aluminum hydride (LiAlH4) reduction 16-dehydrogenation progesterone acetate (1), to obtain 5,16-pregnant diene-3 β, 20-glycol (2), 5,16-pregnant diene-3 β, 20-glycol (2) and diacetyl oxide and tosic acid reaction, obtain 5,17 (20)-anti--pregnant diene-3 β, 16 β-diacetate esters and 5,17 (20)-anti--pregnant diene-3 β, the mixture of 16 α-diacetate esters (3).The mixture of gained reacts with potassium hydroxide in methyl alcohol, obtain 5,17 (20)-anti--pregnant diene-3 β, 16 beta-diols and 5,17 (20)-anti--pregnant diene-3 β, the mixture of 16 salmefamols (4) with aluminium isobutyl or this mixture of phenol aluminaization, obtains the three-dimensional heterogeneous mixture (about 8: 2 of Z: E=) of myrrh sterone thus.

Though known above-claimed cpd (5) has favorable effects, its preparation method is also unsatisfactory, so do not have cost benefit.That is to say,

1) raw material 16-dehydrogenation progesterone is a kind of steroid that is difficult to obtain usually, so it is not suitable for industry.

2) used lithium aluminum hydride (LiAlH in first reduction step ₄) when being exposed in the moisture, can produce hydrogen, hydrogen may set off an explosion, and is breakneck so adopt lithium aluminum hydride with technical scale.

3) used acetate is difficult to handle after reaction is finished in second reaction, and 72 hours reaction times is also oversize.

4) in the 3rd step, longer with potassium hydroxide reaction times of 6 hours of methyl alcohol of refluxing.

5) productive rate of the 3rd reactions steps is 114%, but this patent specification is not mentioned the productive rate of end product myrrh sterone.

6) synthetic method of describing in the above-mentioned patent is insecure, because do not mention the analytical data of myrrh sterone and intermediate thereof in this patent specification.

In this case, need a kind of easy and cheap novel method for preparing single E type or Z type myrrh sterone in this area.

Summary of the invention

The purpose of this invention is to provide a kind of method for preparing guggulusterol, single E-type myrrh sterone (III) and single Z-type myrrh sterone (IV), the raw material of this method is cheap and easy to get, and this method reaction times is short, and productive rate height and cost are low.

In these cases, the inventor furthers investigate the synthetic of myrrh sterone.So, the result, they have found a kind of effective means, and this method is to prepare the represented compound of following general formula (II) by the represented known class sterol of following general formula (I), thus easy and synthetic economically following general formula (III) and (IV) represented myrrh sterone.

Wherein A represent hydroxy (OH) or the oxygen base (=O); B represent hydroxy (OH), the oxygen base (=O) or methyl ketone group (C (O) CH ₃); C represent hydroxy (OH) or the oxygen base (=O); N is an oxygen atomicity, is 0 or 1; Dotted line is illustrated in C-4 and (calls " Δ in the following text ⁴") or C-5 (call " Δ in the following text ⁵") two keys are arranged on the position.

Embodiment

The compound that a target compound of the present invention is a general formula (III) can obtain by the compound of oxidation general formula (II), and the isomerization of compound that can be by general formula (III) obtains the compound of general formula (IV).Explanation earlier is by the method as the compound of the compound general formula (II) of the general formula (I) of raw material, and then above-mentioned preparation method is described.

I. the compound of general formula (II) is synthetic:

I-1. by the 4-androstene-3 of general formula (I), the compound of the synthetic general formula (II-A) of 17-diketone (I-A), in the general formula (I) A and B respectively for epoxy group (=O), n is 0, Δ ⁴:

With 1; the 2-dithioglycol is handled the compound of general formula (I-A); only protecting the locational ketone group of C-3, thereby obtain the compound of general formula (I-A-1), the compound of general formula (I-A-1) obtains the compound of general formula (I-A-2) through Wittig (Wittig) reaction of the locational ketone group of C-17.By removing blocking group, obtain the compound of general formula (I-A-3) to ketone group on Compound C-3 position of above-mentioned general formula (I-A-2).By with tin anhydride (SeO ₂) reaction, make the compound oxidation of general formula (I-A-3), on the C-16 position, introducing alcohol radical, thereby make the guggulusterol of the compound representative of general formula (II-A).

Reaction scheme (1)

The preparation of the compound of [steps A] general formula (I-A-1):

In the presence of an acidic catalyst, the compound of general formula (I-A) and alkane two mercaptan react in solvent, can obtain the compound of general formula (I-A-1).

The used solvent of this reaction can be methylene dichloride, chloroform, 1,2-ethylene dichloride, ether, acetonitrile, tetrahydrofuran (THF), toluene and Glacial acetic acid.These solvents can use separately, also can two or more unite use.Wherein, preferred especially methylene dichloride and Glacial acetic acid.

Can adopt 1 and 1, alkane two mercaptan of the locational conjugation group of C-3 are optionally protected in the conduct of 3-dimercaptopropane, preferred 1.

As Lewis acid, can use boron trifluoride diethyl etherate thing (BF ₃Et ₂O), zinc iodide (ZnI ₂), tellurium chloride (TeCl ₂), magnesium iodide (MgI ₂) and tosic acid (TsOH).Wherein, preferred BF ₃Et ₂O and tosic acid.Used lewis acidic amount is generally 0.1～2.0 equivalent of alkane two amount of mercaptans in this reaction, preferred 0.5～1.0 equivalent.

Temperature of reaction depends on used solvent.Yet, preferably react more preferably 0 ℃～25 ℃ at-10 ℃～80 ℃.Reaction times also depends on temperature of reaction and the used solvent of reaction.But preferred reaction was carried out 30 minutes～12 hours, was more preferably less than 4 hours.

The preparation of the compound of [step B] general formula (I-A-2):

Be the compound of preparation general formula (I-A-2), preferably make the compound and the ethyl triphenyl phosphonium halide (Ph of general formula (I-A-1) ₃P ⁺CH ₂CH ₃X ^-) reaction in the presence of highly basic in non-aqueous solvent.

As non-aqueous solvent, can use ether, tetrahydrofuran (THF), hexane, heptane, methyl alcohol, ethanol, dimethyl sulfoxide (DMSO), benzene, toluene and dimethylbenzene.These solvents can use separately, also can two or more unite use.Wherein, preferred especially ether and tetrahydrofuran (THF).

As ethyl triphenyl phosphonium halide used in the Wittig reaction, can use ethyl triphenyl phosphonium chloride (Ph ₃P ⁺CH ₂CH ₃Cl ^-), ethyl triphenyl phosphonium bromide (Ph ₃P ⁺CH ₂CH ₃Br ^-) and ethyl triphenyl phosphonium iodide (Ph ₃P ⁺CH ₂CH ₃I ^-).Wherein, preferred especially ethyl triphenyl phosphonium bromide and ethyl triphenyl phosphonium iodide.

As the highly basic reagent in the Wittig reaction, it comprises lithium hydride, sodium hydride, potassium hydride KH, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, sodium methoxide, Sodium Ethoxide or uncle's fourth oxygen potassium.Wherein, preferred especially n-Butyl Lithium and uncle's fourth oxygen potassium.

The amount of used alkali is generally 1.0～4.0 equivalents of ethyl triphenyl phosphonium halide, to form inner salt, preferred 1.0～1.5 equivalents.

Temperature of reaction changes because of the type of solvent for use, but is generally-10 ℃～120 ℃.When ethyl triphenyl phosphonium halide and highly basic react in the presence of anhydrous solvent when forming inner salt, this is reflected at-10 ℃～20 ℃ and carries out.When using the compound of general formula (I-A-1) in the Wittig reaction, this is reflected at-10 ℃ and carries out between the boiling point of solvent for use, when solvent is tetrahydrofuran (THF), and preferred-10 ℃～20 ℃.

Reaction times also depends on temperature of reaction and solvent for use.But preferably this reaction was carried out 30 minutes to 1 day, was more preferably less than 2 hours.

The preparation of the compound of [step C] general formula (I-A-3)

By the blocking group of ketone group on Compound C-3 position of removing general formula (I-A-2), can obtain the compound of general formula (I-A-3).

Suitable solvent in the described protective reaction comprises distilled water, acetone, chloroform, methylene dichloride, acetonitrile, tetrahydrofuran (THF) and Glacial acetic acid.These solvents can use separately, also can two or more unite use.Wherein, preferred especially tetrahydrofuran (THF) and Glacial acetic acid.

As reagent used in the protective reaction, can use Silver Nitrate (AgNO ₂), N-bromo-succinimide (NBS), iodine and tin anhydride (SeO ₂).These reagent can use separately, also can two or more unite use.Wherein, preferred especially Silver Nitrate and iodine and tin anhydride.

Describedly go to protect the amount of reagent to depend on agents useful for same.Yet, preferably adopt 0.5～3.0 equivalent of the compound amount of general formula (I-A-2), preferred 0.5～1.5 equivalent.

Temperature of reaction depends on solvent for use and reagent.Yet preferred reaction is carried out at-10 ℃～100 ℃, more preferably 10 ℃～65 ℃.Reaction times also depends on the type of temperature of reaction and agents useful for same, but is generally 30 minutes to 1 day, preferably is less than 3 hours.

The preparation of the guggulusterol of [step D] general formula (II-A).

Make the compound and the tin anhydride (SeO of general formula (I-A-3) ₂) and hydrogen peroxide in solvent, react, can obtain the guggulusterol of general formula (II-A).

The amount of tin anhydride is generally 0.1～2.0 equivalent of the compound of general formula (I-A-3), preferred 0.25～1.0 equivalent.

As superoxide, can use hydrogen peroxide, tert-butyl peroxide, N-methylmorpholine N-oxide compound (NMO) or N-pyridine oxide (C ₅H ₅N-O).Wherein, special preferred tertiary butylperoxide.The amount of hydrogen peroxide is generally 0.5～3.0 equivalent of the compound of general formula (I-A-3), preferred 1.0～2.0 equivalents.

As the sprotic polar solvent that is used for this step, can select N for use, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), pyridine, acetonitrile, acetone, ethyl acetate, tetrachloroethane, chloroform and methylene dichloride.As ether, can provide tetrahydrofuran (THF), dioxane, glycol dimethyl ether, diglyme and triglyme.As aromatic hydrocarbons, can use benzene, toluene and dimethylbenzene.Wherein, preferred sprotic polar solvent and ether.More specifically, preferred methylene dichloride and preferred dioxane.

Temperature of reaction depends on solvent for use.Yet preferred reaction is carried out at-10 ℃～80 ℃, more preferably 10 ℃～30 ℃.Reaction times also changes because of the type of temperature of reaction and solvent for use, and still this reaction was carried out 30 minutes～12 hours usually, preferably was less than 2 hours.

I-2. by the compound of the synthetic general formula (II-B) of the 5-androstene-3-alcohol-17-ketone [DHEA (I-B)] of general formula (I), A representation hydroxy in the general formula (I) (OH), B be the oxygen base (=O), n is 0, Δ ⁵:

Shown in following reaction scheme 2, do not protect the locational alcohol radical of C-3, make the locational ketone group generation of the C-17 Wittig reaction of the compound of general formula (I-B), can obtain the compound of general formula (I-B-1).Make the compound and the tin anhydride (SeO of general formula (I-B-1) ₂) reaction, can obtain the compound of general formula (II-B), thereby on the C-16 position, introduce alcohol radical.

Reaction scheme (2)

The preparation of the compound of [step e] general formula (I-B-1)

For obtaining the compound of general formula (I-B-1), preferably make the compound and the ethyl triphenyl phosphonium halide (Ph of general formula (I-B) ₃P ⁺CH ₂CH ₃X ^-) in the presence of highly basic, in non-aqueous solvent, react, do not protect the locational alcohol radical of C-3 this moment.

As non-aqueous solvent, can use ether, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), benzene, toluene and dimethylbenzene.These solvents can use separately, also can two or more unite use.Wherein, preferred especially tetrahydrofuran (THF) and dimethyl sulfoxide (DMSO).

As highly basic reagent, can use lithium hydride, sodium hydride, potassium hydride KH, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, Sodium Ethoxide and uncle's fourth oxygen potassium.Wherein, preferred especially sodium hydride, n-Butyl Lithium and uncle's fourth oxygen potassium.

The amount of used alkali is generally 1.0～4.0 equivalents of ethyl triphenyl phosphonium bromide, to form inner salt, preferred 1.0～1.2 equivalents.

Temperature of reaction depends on the solvent for use type, but preferred usually preferred reaction is usually carried out at-10 ℃～120 ℃.If the ethyl triphenyl phosphonium bromide reacts in non-aqueous solvent in the presence of highly basic to generate inner salt, then preferred reaction is carried out at-10 ℃～20 ℃, if the compound of general formula (I-B) carries out Wittig reaction, then this is reflected at-10 ℃ and carries out to the temperature between the boiling point of solvent for use.When during as solvent, preferably carrying out,, then preferably carry out at 25 ℃～80 ℃ if use dimethyl sulfoxide (DMSO) at 25 ℃～40 ℃ with tetrahydrofuran (THF).

Reaction times also changes because of temperature of reaction and agents useful for same type, but is generally 30 minutes to 1 day, preferably is less than 2 hours.

The preparation of the compound of [step F] general formula (II-B)

Make the compound and the tin anhydride (SeO of general formula (I-B-1) ₂) and hydrogen peroxide in solvent, react, can obtain the compound of general formula (II-B).

Tin anhydride (SeO ₂) amount be generally 0.1～3.0 equivalent of the compound of general formula (I-B-1), preferred 0.5～1.5 equivalent.

As superoxide, can use hydrogen peroxide, tert-butyl peroxide, N-methylmorpholine N-oxide compound and N-pyridine oxide.Wherein, special preferred tertiary butylperoxide.The amount of hydrogen peroxide is generally 0.5～4.0 equivalent of the compound of general formula (I-B-1), preferred 1.0～2.0 equivalents.

As used sprotic polar solvent in this reaction, can use N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), pyridine, acetonitrile, acetone, ethyl acetate, tetrachloroethane, chloroform and methylene dichloride.As ether, can be to provide tetrahydrofuran (THF), dioxane, glycol dimethyl ether, diglyme and triglyme.As aromatic hydrocarbons, can use benzene, toluene and dimethylbenzene.Wherein, preferred sprotic polar solvent and ether.More specifically, preferred methylene dichloride and preferred dioxane.

Temperature of reaction changes because of the type of agents useful for same, but reaction is carried out preferred-10 ℃～10 ℃ usually at-10 ℃～80 ℃.Reaction times also changes because of temperature of reaction and agents useful for same type, but reaction carried out 30 minutes to 12 hours usually, preferably is less than 4 hours.

I-3. by the compound of the synthetic general formula (II-A) of the 5-androstene-3-alcohol-17-ketone [DHEA (I-B)] of general formula (I), in the general formula (I), the A representation hydroxy (OH), B be the oxygen base (=O), n is 0, Δ ⁵:

The locational ketone group generation of the C-17 Wittig reaction of the compound of general formula (I-B); do not protect the locational alcohol radical of C-3 this moment; can obtain the compound of general formula (I-B-1); then it is used pyridinium chlorochromate (PCC) oxidation, form the compound that has the general formula (I-B-2) of ketone group on the C-3 position.Two keys of the compound of general formula (I-B-2) shift in the presence of alkali, form the compound of general formula (I-B-3), the compound of general formula (I-B-3) then and the tin anhydride reaction introducing alcohol radical on the C-16 position, thereby obtains the compound guggulusterol of general formula (II-A).

Reaction scheme (3)

The preparation of the compound of [step G] general formula (I-B-2)

The compound and the oxidant reaction of general formula (I-B-1) can obtain the compound of general formula (I-B-2).

In this oxidising process, can use pyridinium chlorochromate (PCC), dichromic acid pyridine (PDC), Jones's (Jones) reagent and Swern oxygenant (forming), so that the locational secondary alcohol groups of C-3 is oxidized to ketone group by DMSO+ClCOCOCl.Wherein, preferred pyridinium chlorochromate.

Solvent for use changes because of the type of oxygenant.Preferred methylene dichloride and pyridinium chlorochromate (PCC), N,N-dimethylacetamide and dichromic acid pyridine (PDC), acetone and Jones reagent and methylene dichloride and Swern oxygenant.

The amount of oxygenant changes because of the type of oxygenant.The amount of chromium oxygenant is generally 1.0～5.0 equivalents of the compound of general formula (I-B-1), preferred 1.2～2.0 equivalents.

In the Swern oxidizing reaction, the amount that is used to prepare the dimethyl sulfoxide (DMSO) of oxygenant is preferably 1.0～3.0 equivalents of the compound of general formula (I-B-1), and the amount of oxalyl chloride is preferably 1.0～1.5 equivalents of the compound of general formula (I-B-1).

Temperature of reaction changes because of the type of oxygenant, but is generally-78 ℃～30 ℃.If use the chromium oxygenant, then preferred reaction is carried out at-10 ℃～10 ℃, and when adopting the Swern oxidizing reaction, then preferred reaction is carried out at-78 ℃～30 ℃.

Reaction times also changed because of oxidation reaction method, but preferred reaction was carried out 30 minutes to 12 hours usually, more preferably less than 2 hours.

The preparation of the compound of [step H] general formula (I-B-3)

The generation double-bond migration reaction of the compound by making general formula (I-B-2) with alkali can obtain the compound of general formula (I-B-3).

As available solvent in this reaction, can use methyl alcohol, ethanol, ether, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), benzene and toluene.Special particular methanol and tetrahydrofuran (THF).

As used alkali in the elimination reaction of ketone group α-hydrogen, can use sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium hydride, sodium hydride, potassium hydride KH, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, sodium methoxide, Sodium Ethoxide and uncle's fourth oxygen potassium.Wherein, preferred especially sodium hydroxide, potassium hydroxide and uncle's fourth oxygen potassium.The amount of alkali is equivalent to 1.0～4.0 equivalents of the compound amount of general formula (I-B-2) usually, preferred 1.0～1.5 equivalents.

Temperature of reaction changes because of the type of used alkali and solvent, but preferred reaction is carried out more preferably 10 ℃～50 ℃ at-10 ℃～120 ℃ usually.

The type of reaction times because of temperature of reaction and used alkali and solvent changes, but is generally 30 minutes to 4 hours, preferably is less than 1 hour.

I-4. by the compound of the synthetic general formula (II-A) of the testosterone (I-C) of general formula (I), in the general formula (I) A be the oxygen base (=O), B is that (OH), n is 0 to hydroxyl, Δ ⁴:

In reaction scheme 4, the compound and the 1 of general formula (I-C) react in the presence of an acidic catalyst, obtain the compound of general formula (I-C-1).Wittig reaction takes place in this compound and ethyl triphenyl phosphonium halide in the presence of highly basic, obtain the compound of general formula (I-C-3).Then; the ketone group of the compound by general formula (I-C-3) go protection, obtain the compound of general formula (I-A-3), use the compound of tin anhydride oxidation general formula (I-A-3) then; on the C-16 position, introducing alcohol radical, thereby form the compound guggulusterol of general formula (II-A).

Reaction scheme (4)

The preparation of the compound of [step I] general formula (I-C-1)

Compound for preparation general formula (I-C-1) reacts the compound of general formula (I-C) and 1 in solvent in the presence of an acidic catalyst.

As solvent, can use chloroform, methylene dichloride, tetrachloroethane, tetrahydrofuran (THF), acetonitrile, benzene and toluene.Wherein, preferred especially methylene dichloride and benzene solvent.

As alkyl diol, can use 1 (ethylene glycol) and 1, ammediol.Wherein, preferred especially 1.

The available an acidic catalyst comprises boron trifluoride diethyl etherate thing (BF in this reaction ₃Et ₂O), zinc iodide, oxalic acid and tosic acid.Wherein, preferred especially tosic acid.The amount of used acid is generally 0.01～2.0 equivalent of alkyl diol, preferred 0.01～0.05 equivalent.

Temperature of reaction changes because of the type of agents useful for same, but preferred reaction is carried out more preferably 70 ℃～100 ℃ at-10 ℃～110 ℃ usually.Reaction times changes because of temperature of reaction and agents useful for same type, but reaction carried out 30 minutes to 12 hours usually, preferably is less than 3 hours.

The preparation of the compound of [step J] general formula (I-C-2).

The compound of general formula (I-C-1) and chromic oxide react, and can obtain the compound of general formula (I-C-2).

In this oxidising process, can the locational secondary alcohol groups of C-17 be oxidized to ketone group with pyridinium chlorochromate (PCC) and dichromic acid pyridine (PDC).Wherein, preferred pyridinium chlorochromate.

Solvent for use changes because of the type of oxygenant.Preferred methylene dichloride and pyridinium chlorochromate (PCC), N,N-dimethylacetamide and dichromic acid pyridine (PDC).

The amount of oxygenant changes because of the type of oxygenant, but is generally 1.0～5.0 equivalents of the compound of general formula (I-C-1), preferred 1.5～2.0 equivalents.

Temperature of reaction changes because of oxidant type, but is generally-10 ℃～30 ℃.Reaction times also changes because of the type of oxygenant.But preferred reaction was carried out 30 minutes to 12 hours usually, more preferably less than 2 hours.

The preparation of the compound of [step K] general formula (I-C-3)

Be the compound of preparation general formula (I-C-3), preferably make the compound and the ethyl triphenyl phosphonium halide (Ph of general formula (I-C-2) ₃P ⁺CH ₂CH ₃X ^-) in the presence of highly basic, in non-aqueous solvent, react.

The non-aqueous solvent that is suitable in this reaction comprises ether, tetrahydrofuran (THF), hexane, heptane, methyl alcohol, ethanol, dimethyl sulfoxide (DMSO), benzene,toluene,xylene and dimethyl sulfoxide (DMSO).These solvents can use separately, also can two or more unite use.Wherein, preferred especially tetrahydrofuran (THF) and dimethyl sulfoxide (DMSO).

The ethyl triphenyl phosphonium halide that is suitable in the Wittig reaction comprises ethyl triphenyl phosphonium chloride (Ph ₃P ⁺CH ₂CH ₃Cl ^-), ethyl triphenyl phosphonium bromide (Ph ₃P ⁺CH ₂CH ₃Br ^-) or ethyl triphenyl phosphonium iodide (Ph ₃P ⁺CH ₂CH ₃I ^-).Wherein, preferred especially ethyl triphenyl phosphonium bromide and ethyl triphenyl phosphonium iodide.

The highly basic reagent that is suitable in the described Wittig reaction comprises lithium hydride, sodium hydride, potassium hydride KH, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, sodium methoxide, Sodium Ethoxide and uncle's fourth oxygen potassium.Wherein, preferred especially sodium hydride and uncle's fourth oxygen potassium.

The amount of alkali is generally 1.0～4.0 equivalents of ethyl triphenyl phosphonium halide with the formation inner salt, but the amount of preferred bases is 1.0～1.5 equivalents of ethyl triphenyl phosphonium halide usually.

Temperature of reaction changes because of the type of solvent for use, but is generally-10 ℃～120 ℃.If reaction forms inner salt in the non-aqueous solvent of ethyl triphenyl phosphonium halide in the presence of highly basic, then be reflected at-10 ℃～20 ℃ and carry out, if the compound of general formula (I-C-2) carries out Wittig reaction, then be reflected at 25 ℃～100 ℃ and carry out.Preferably, if solvent is a tetrahydrofuran (THF), then temperature of reaction is 50 ℃～70 ℃, if solvent is a dimethyl sulfoxide (DMSO), then temperature of reaction is 20 ℃～80 ℃.

The type of reaction times because of temperature of reaction and solvent for use changed, but preferred reaction was carried out 30 minutes to 1 day usually, more preferably less than 2 hours.

The preparation of the compound of [step L] general formula (I-A-3)

By removing the locational ketone group blocking group of Compound C-3 of general formula (I-C-3), can obtain general formula (I-A-3) compound.

The solvent that is suitable in this protective reaction comprises distilled water, acetone, chloroform, methylene dichloride, acetonitrile, tetrahydrofuran (THF) and Glacial acetic acid.These solvents can use separately, also can two or more unite use.Wherein, the mixed solvent of preferred especially distilled water and acetone.

As agents useful for same in the protective reaction, can use tosic acid pyridine (PPTS), tosic acid (TsOH), hydrochloric acid and Glacial acetic acid.Wherein, preferred especially tosic acid pyridine (PPTS).

The amount of reagent changes because of the agents useful for same type, but is generally 0.05～0.5 equivalent of the compound of general formula (I-C-3), preferred 0.1～0.3 equivalent.

Temperature of reaction changes because of the type of solvent for use and reagent, but is generally 0 ℃～100 ℃, preferred 30 ℃～60 ℃.Reaction times also changes because of temperature of reaction and agents useful for same type, but is generally 30 minutes to 1 day, preferably is less than 3 hours.

I-5. by 16 α of general formula (I), 17 α-epoxypregnenolone (I-D) synthesize the compound of general formula (II-B), and A is that (OH), B is methyl ketone group (C (O) CH to hydroxyl in the general formula (I) ₃), n is 1, Δ ⁵:

In reaction scheme 5, the compound of general formula (I-D) and hydrazine (NH ₂NH ₂) reaction at high temperature in the presence of alkali, thereby the compound of synthetic general formula (II-B), wherein C is hydroxyl (OH) a, Δ ⁵

Reaction scheme (5)

The preparation of the compound of [step M] general formula (II-B)

In the method, can use hydrazine (NH ₂NH ₂) monohydrate and hydrazine (NH ₂NH ₂) acid anhydride.Wherein, preferred hydrazine monohydrate.The amount of used hydrazine is 1.0～40 equivalents of the compound of general formula (I-D), preferably is equivalent to as 1.5～2.5 equivalents of the organometallic reagent of alkali with as 10～20 equivalents of the alkali metal hydroxide of alkali.

The solvent that is suitable in this reaction comprises methyl alcohol, ethanol, butanols, ether, tetrahydrofuran (THF), 1,4-dioxane, dimethyl sulfoxide (DMSO), benzene,toluene,xylene, diglyme, diethylene glycol monomethyl ether and glycol ether.Wherein, preferred especially tetrahydrofuran (THF) and glycol ether.

As used alkali, can use sodium hydroxide, potassium hydroxide, lithium hydroxide, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, diisopropylamine lithium, diisopropylamino potassium, sodium methoxide, Sodium Ethoxide and uncle's fourth oxygen potassium.Wherein, preferred sodium hydroxide, potassium hydroxide and diisopropylamino potassium.The amount of used alkali changes because of the type of used alkali, but when preferably adopting alkali metal hydroxide 2.0～15 equivalents, when adopting alkalimetal hydride is 1.0～3.0 equivalents, is 1.0～3.0 equivalents when adopting organometallic reagent, is 1.0～4.0 equivalents when adopting alkali metal alcoholate.

Temperature of reaction changes because of the type of solvent for use and alkali, but is generally-100 ℃～190 ℃, for alkalimetal hydride and organometallic reagent, preferably-100 ℃～-78 ℃, for alkali metal alcoholate, preferred 20 ℃～100 ℃, preferred 80 ℃～160 ℃ for alkali metal hydroxide.Reaction times also changed because of the type of temperature of reaction and used alkali, but preferred reaction was carried out 30 minutes to 48 hours usually, more preferably less than 4 hours.

1-6. by the compound of the synthetic general formula (II-A) of the progesterone of general formula (I-E), wherein A be the oxygen base (=O), B is ketone base (C (O) CH ₃), n is 0, Δ ⁴:

In reaction scheme 6, the C-3 and the locational ketone group of C-20 of the compound of general formula (I-E) are reduced to its alcohol, obtain the compound of general formula (I-E-1), then, make this compound and have optionally oxidant reaction, thereby the locational alcohol radical of C-3 is oxidized to ketone group, obtains the compound of general formula (I-E-2).By introduce on the locational alcohol radical of C-20 obtain the compound of general formula (I-E-3) as the p-toluenesulfonyl of leavings group or methylsulfonyl after; the compound and the alkali reaction of general formula (I-E-3); form the compound of general formula (I-E-4), the compound of general formula (I-E-4) is the heterogeneous mixture of E and Z.The reaction of this mixture and tin anhydride by introducing alcohol radical on the C-16 position, thereby obtains the compound guggulusterol of general formula (II-A).

Reaction scheme (6)

The preparation of the compound of [step N] general formula (I-E-1)

The compound of general formula (I-E) and reductive agent react, thereby obtain the compound of general formula (I-E-1).

The solvent that is suitable in this reaction comprises methyl alcohol, ethanol, ether, tetrahydrofuran (THF) and methylene dichloride.Wherein, special particular methanol and ethanol.

As reductive agent used in the ketone reduction reaction, can use lithium aluminum hydride (LAH), diisobutyl aluminium hydride (DIBAL-H), sodium borohydride (NaBH in the hydro-reduction reaction ₄), lithium borohydride (LiBH ₄) and platinum catalyst.Wherein, preferred borohydride reduction agent, preferred especially sodium borohydride (NaBH ₄).The amount of reductive agent is generally 0.5～4.0 equivalent of the compound of general formula (I-E), preferred 1.5～2.5 equivalents.

Temperature of reaction changes because of the type of solvent for use and reductive agent, but is generally-100 ℃～60 ℃, preferred-78 ℃～25 ℃.Reaction times changes because of temperature of reaction and solvent for use type, but preferred reaction was carried out 30 minutes to 6 hours usually, preferably was less than 2 hours.

The preparation of the compound of [step O] general formula (I-E-2)

The compound of general formula (I-E-1) with have optionally oxidant reaction, can obtain the compound of general formula (I-E-2).

In the method, can adopt activated manganese dioxide (MnO ₂) come optionally oxidation alcohol radical.The amount of oxygenant is generally 1-0～40 equivalents of the compound of general formula (I-E-1), preferred 10～20 equivalents.

The solvent that is suitable in this reaction comprises pentane, hexane, heptane, sherwood oil, benzene,toluene,xylene, acetone, chloroform, methylene dichloride and tetrachloroethane.Wherein, preferred especially methylene dichloride.

Temperature of reaction changes because of the type of solvent for use, but is generally-10 ℃～100 ℃, preferred 20 ℃～50 ℃.The type of reaction times because of temperature of reaction and solvent for use changed, but preferred reaction was carried out 30 minutes to 12 hours usually, more preferably less than 2 hours.

The preparation of the compound of [step P] general formula (I-E-3)

The compound of general formula (I-E-2) and Tosyl chloride or methylsulfonyl chloride react in the presence of alkali, can obtain the compound of general formula (I-E-3).

In this reaction, can use Tosyl chloride or methylsulfonyl chloride, the amount of this reagent is generally 1.0～4.0 equivalents of the compound of general formula (I-E-2), preferred 2.0～3.0 equivalents.

The solvent that this reaction is suitable for comprises N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, acetone, ethyl acetate, tetrahydrofuran (THF), tetrachloroethane, chloroform, methylene dichloride, benzene, toluene or pyridine.Wherein, preferred methylene dichloride and pyridine.

As used alkali, can use pyridine, triethylamine, imidazoles and N, the N-dimethyl aminopyridine.Wherein, preferred pyridine and N, N-dimethyl aminopyridine.The amount of this alkali is generally 1.0～4.0 equivalents of the compound of general formula (I-E-2), preferred 1.5～2.5 equivalents.

Temperature of reaction changes because of the type of agents useful for same, but is generally-10 ℃～40 ℃, preferred 0 ℃～25 ℃.The type of reaction times because of temperature of reaction and solvent for use changed, but preferred reaction was carried out 1 hour to 1 day usually, more preferably less than 5 hours.

The preparation of the compound of [step Q] general formula (I-E-4)

The compound of general formula (I-E-3) and highly basic react, and can obtain the compound of general formula (I-E-4).

As the used alkaline reagents of this reaction, can use sodium hydride, potassium hydride KH, sodium methoxide, Sodium Ethoxide, uncle's fourth oxygen potassium, pyridine, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene and 1, the amine salt of 8-diazabicyclo [5.4.0] 11 carbon-7-alkene.Wherein, preferred sodium methoxide and pyridine.The amount of this alkali is generally 1.0～4.0 equivalents of the amount of each alkalimetal hydride, alkali metal alcoholate and amine salt.Pyridine can be used as solvent, also can be used as reactant.

The solvent that this reaction is suitable for comprises N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, methyl alcohol, ethanol, butanols, tetrahydrofuran (THF), tetrachloroethane, chloroform, methylene dichloride, benzene, toluene and pyridine.Wherein, preferred dimethyl sulfoxide (DMSO), methyl alcohol and pyridine.

Temperature of reaction changes because of the type of solvent for use and alkali, but is generally-78 ℃～150 ℃, preferred 25 ℃～120 ℃.The type of reaction times because of temperature of reaction and used alkali changed, but reaction was carried out 1 hour to 1 day usually, more preferably less than 5 hours.

II. the compound of general formula (III) is synthetic:

II-1. compd E-type myrrh the sterone that synthesizes general formula (III) by the guggulusterol of general formula (II-A):

In reaction scheme 7, the compound and the oxidant reaction of general formula (II-A) can obtain the compd E-type myrrh sterone of general formula (III).

Reaction scheme (7)

The preparation of the compd E of [step R] general formula (III)-type myrrh sterone

The guggulusterol and the oxidant reaction of general formula (II-A) can obtain the E-type myrrh sterone of general formula (III).

As the oxygenant that is used for secondary alcohol groups is oxidized to ketone group, can adopt pyridinium chlorochromate (PCC), dichromic acid pyridine (PDC), Jones reagent and activated manganese dioxide.Wherein, preferred Jones reagent and activated manganese dioxide.Preferred especially activated manganese dioxide.

The solvent that is suitable in this reaction comprises pentane, hexane, heptane, sherwood oil, benzene,toluene,xylene, dimethyl sulfoxide (DMSO), acetone, chloroform, methylene dichloride, tetrachloroethane, ether and tetrahydrofuran (THF).Wherein, preferred methylene dichloride.Can not have under the situation of solvent activated manganese dioxide to be used for this reaction.

The amount of oxygenant changes because of the type of used oxygenant, but is generally 1.0～20 equivalents of the compound of general formula (II-A), is preferably 5.0～10 equivalents of activated manganese dioxide.

Temperature of reaction changes because of the type of agents useful for same, but is generally-10 ℃～100 ℃, preferred 20 ℃～50 ℃.Reaction times changed because of temperature of reaction and agents useful for same class, but preferred reaction was carried out 30 minutes to 12 hours usually, more preferably less than 2 hours.

II-2. compd E-type myrrh the sterone that synthesizes general formula (III) by the compound of general formula (II-B):

In reaction scheme 8, the compound and the oxidant reaction of general formula (II-B) can obtain the compd E-type myrrh sterone of general formula (III).

Reaction scheme (8)

The preparation of the E type myrrh sterone of [step S] general formula (III)

The compound of general formula (II-B) and aluminium oxidant can obtain the myrrh sterone of general formula (III) by Oppenauer (Oppenauer) oxidizing reaction.

As aluminium oxidant used in the Oppenauer oxidizing reaction, can use aluminium isopropoxide (Al[OCH (CH ₃) ₂] ₃), tri sec-butoxy aluminum (Al[OCH (CH ₃) CH ₂CH ₃] ₃), three tert.-butoxy aluminium (Al[OC (CH ₃) ₃] ₃), triple phenoxyl aluminium (Al[OC ₆H ₅] ₃).Wherein, preferred aluminium isopropoxide.The amount of aluminum oxide is 0.3～1.5 equivalent of the compound of general formula (II-B) normally, preferred 0.5～1.0 equivalent.

The non-aqueous solvent that is suitable in this reaction comprises benzene,toluene,xylene and 1.Wherein, preferred benzene and toluene.

As the used reductive agent of Oppenauer oxidizing reaction, can use acetone, methylethylketone, methyl phenyl ketone, benzophenone and pimelinketone.Wherein, preferred methylethylketone and pimelinketone.

Temperature of reaction changes because of the type of agents useful for same, but is generally 50 ℃～180 ℃.Temperature of reaction can influence the regioselectivity of end product myrrh sterone.Carry out if be reflected at 50 ℃～100 ℃, then have to E-type myrrh sterone, and be reflected at 120 ℃～180 ℃ when carrying out, then obtain the mixture of E type and Z type-myrrh sterone.

The type of reaction times because of temperature of reaction and solvent for use changed, but preferred reaction was carried out 30 minutes to 4 hours usually, more preferably less than 2 hours.

III. the compound that synthesizes general formula (IV):

The compound Z-type myrrh sterone that synthesizes general formula (IV) by the compd E-type myrrh sterone of general formula (III):

In reaction scheme 9, the E-type myrrh sterone of general formula (III) can obtain the Z-type myrrh sterone of general formula (IV) by photochemical reaction, thermal chemical reaction or acid catalyzed reaction.

Reaction scheme (9)

The preparation of the Z-myrrh sterone of [step T] general formula (IV)

As the photochemically reactive photosensitizers of E-type myrrh sterone, can use methylenum coeruleum, methylene green and rose-red.The amount of photosensitizers is 0.01～0.2 equivalent of the compound of general formula (III) normally, preferred 0.05～0.1 equivalent.

As light source, can use the tungsten lamp of 60W～500W usually, but preferably use the tungsten lamp of 150W～300W.

The solvent that is suitable in this photochemical reaction comprises distilled water, methyl alcohol, ethanol, acetonitrile, acetone, tetrachloroethane, chloroform, methylene dichloride, tetrahydrofuran (THF), benzene, toluene and dimethylbenzene.These solvents can use separately, also can two or more unite use.Wherein, preferred methylene dichloride, chloroform, acetonitrile, methyl alcohol and ethanol.Preferred especially chloroform and methyl alcohol.

Temperature of reaction changes because of the type of agents useful for same, but is generally-10 ℃～100 ℃, preferred 20 ℃～50 ℃.

The type of reaction times because of intensity, temperature of reaction and the used photosensitizers of light source changed, but preferred reaction was carried out l hour to 48 hours usually, more preferably less than 10 hours.

The solvent that is suitable in this thermal chemical reaction comprises benzene,toluene,xylene and 1.Wherein, preferred toluene.

Temperature of reaction changes because of the type of solvent for use, but is generally 80 ℃～200 ℃, preferred 100 ℃～130 ℃.

Reaction times changed because of temperature of reaction and solvent for use type, but preferred reaction was carried out 1 hour to 48 hours usually, more preferably less than 2 hours.

As an acidic catalyst used in this acid catalyzed reaction, can use tosic acid and dilute hydrochloric acid (0.1～3.0N HCl).The amount of an acidic catalyst is 0.01～0.5 equivalent of the compound of general formula (III), preferred 0.05～0.2 equivalent.

The solvent that is suitable in this acid catalyzed reaction comprises acetonitrile, acetone, tetrachloroethane, chloroform, methylene dichloride, tetrahydrofuran (THF), benzene, toluene and dimethylbenzene.These solvents can use separately, also can two or more unite use.Wherein, preferred methylene dichloride, chloroform, acetonitrile, benzene and toluene.More preferably respectively chloroform and benzene are used for tosic acid, acetonitrile is used for dilute hydrochloric acid.

Temperature of reaction changes because of the type of solvent for use, but is generally-10 ℃～160 ℃, preferred 30 ℃～80 ℃.

Reaction times changed because of temperature of reaction and used an acidic catalyst type, but preferred reaction was carried out 30 minutes to 10 hours usually, more preferably less than 1 hour.

The compound Z-type myrrh sterone of the compd E of known general formula (III)-type myrrh sterone and general formula (VI) is the medicine of treatment people's hyperlipidaemia.

Embodiment

To more specifically explain the present invention by following embodiment.Yet should be appreciated that these embodiment can't limit the present invention by any way.

Embodiment 1: ring-3-(ethylene the dithioacetals)-4-androstene-17-ketone [steps A] that is synthesized general formula (I-A-1) by the compound of general formula (I-A)

25 ℃ with 4-androstene-3,17-diketone (I-A) (28.6g 100mmol) is dissolved in Glacial acetic acid (100ml) fully, again with 1 (10.4ml, 110mmol) and tosic acid (8.6g 50mmol) adds above-mentioned solution continuously.This reaction mixture is further reaction at room temperature, and the mixture of gained is poured in the distilled water (100ml), at room temperature fully stirs 15 minutes then.(mixture of 3 * 50ml) extraction gained with salt solution and distilled water wash organic layer, is used dried over mgso with ethyl acetate, filter and reduction vaporization, adopt ethyl acetate/hexane (2/8) through the column chromatography purifying gained resistates, thereby obtain title compound (27.2g, productive rate: 75%).

¹H NMR (300MHz, CDCl ₃): 5.51 (s, 1H), 3.37 (m, 3H), 3.23 (m, 1H), 2.39 (q, 1H), 2.17-0.84 (steroid main body and 1.04 (s, 3H), 0.88 (s, 3H)=24H)

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

Embodiment 2: by ring-3-(ethylene the dithioacetals)-4-androstene-17-ketone [steps A] of the synthetic general formula (I-A-1) of general formula (I-A)

0 ℃ with 4-androstene-3, (28.6g 100mmol) is dissolved in anhydrous methanol (150ml) to 17-diketone (I-A) fully, and (15ml 179mmol) adds this solution, then, slowly adds an acidic catalyst BF3 ether (14ml) with 1 again.Continue reaction 10 hours at 20 ℃.After this reaction is finished, gained mixture reduction vaporization to remove methyl alcohol, is used the NaHCO of methylene dichloride (100ml) and 5% ₃Solution-treated gained mixture., filter and reduction vaporization, thereby obtain title compound (33.4g, productive rate: 92%) the organic layer drying with sal epsom.

Embodiment 3: by ring-3-(ethylene dithioacetals)-4,17 (20)-suitable-androstene [step B] of the synthetic general formula (I-A-2) of general formula (I-A-1)

(44.6g 120mmol) is dissolved in dried tetrahydrofuran (THF) (200ml), 120ml (120mmol) with the ethyl triphenyl phosphonium bromide at 0 ℃.With 15 minutes slow anhydrous tetrahydro furans (1mol solution) that are dissolved with uncle's fourth oxygen potassium that add in above-mentioned solution.After waiting to add, this reaction mixture at room temperature further reacted 30 minutes, and (33.4g, tetrahydrofuran (THF) 92.1mmol) (150ml) at room temperature slowly add wherein, this reaction mixture are at room temperature stirred 2 hours so that further reaction will to be dissolved with the compound of general formula (I-A-1).With gained mixture reduction vaporization, add the mixed solvent of 250ml hexane and ethyl ester (v/v=10/1), generate by product triphenylphosphine oxide (Ph ₃P=O) throw out filters precipitation is removed.With salt solution and distilled water wash organic layer, use dried over mgso, filtration under diminished pressure then, thus obtain title compound (33.1g, productive rate: 96%).

¹H-NMR (300MHz, CDCl ₃): 5.51 (s, 1H), 5.11 (m, 1H), 3.40 (m, 3H), 3.25 (m, 1H), 2.21-0.77 (steroid main body and 1.05 (s, 3H), 0.91 (s, 3H)=28H)

¹³C-NMR(75.5MHz，CDCl ₃)：150.5，146.9，124.5，113.8，66.3，56.2，54.5，44.6，40.4，40.0，38.5，37.7，37-4，37.1，35.7，33.0，32.5，31.8，24.8，21.8，18.9，17.2，13.5

Embodiment 4: by ring-3-(ethylene dithioacetals)-4,17 (20)-suitable-androstene [step B] of the synthetic general formula (I-A-2) of general formula (I-A-1)

15 ℃ with the ethyl triphenyl phosphonium bromide (37.1g 100mmol) is dissolved in anhydrous dimethyl sulphoxide (150ml), again to wherein slowly add sodium hydride (2.5g, 105mmol).After adding, reaction mixture was at room temperature stirred 30 minutes, at room temperature slowly add then general formula compound (I-A-1) (30g, 82.7mmol).This reaction mixture was at room temperature stirred 2 hours.After reaction is finished, pour salt solution (200ml) and ethyl acetate (200ml) into this reaction mixture, and separate organic layer.With the organic layer dried over mgso, filter and reduction vaporization.Hexane and ethyl ester (v/v=10/1) mixture (250ml) are added in the gained resistates, generate by product triphenylphosphine oxide (Ph ₃P=O) throw out filters precipitation is removed.Removal of solvent under reduced pressure, thus title compound (28.2g, productive rate: 91%) obtained.

Embodiment 5: 4,17 (20)-suitable-pregnant diene-3-ketone that is synthesized general formula (I-A-3) by the compound of general formula (I-A-2)) [step C]

At room temperature with the compound of general formula (I-A-2) (33g 88mmol) is dissolved in Glacial acetic acid (200ml), in said mixture, add immediately tin anhydride (4.8g, 44mmol).The reaction mixture of gained was at room temperature stirred 2 hours, slowly add distilled water (300ml) then.With reaction mixture with ethyl acetate (200ml) extraction three times, and with 10% NaHCO ₃Organic layer after solution washing merges.With this organic layer dried over mgso, filter, and reduction vaporization is to dry.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel,, thereby obtain title compound (21.8g, productive rate: 83%) with ethyl acetate/hexane (v/v=3/7) wash-out.

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

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

Embodiment 6: 4,17 (20)-suitable-pregnant diene-3-ketone [step C] that is synthesized general formula (I-A-3) by the compound of general formula (I-A-2)

At room temperature (4.7g, 30mmol) adding is dissolved with in the distilled water (200ml) of 5% tetrahydrofuran (THF) with 3.8g iodide (15mmol), then stirs 1 hour with Silver Nitrate.At room temperature (30g 80mmol) slowly adds above-mentioned reaction mixture, at room temperature stirs then 3 hours with the compound of general formula (I-A-2).Add saturated sodium thiosulfite (sodium thiosulfide) aqueous solution at 0 ℃, and use ethyl acetate extraction.With the organic layer dried over mgso, filter, and reduction vaporization.Adopt ethyl acetate/hexane (v/v=3/7) through the column chromatography purifying resistates of gained, thereby obtain title compound (21g, productive rate: 88%).

Embodiment 7: E-guggulusterol [the pregnant diene of 4,17 (20)-E--3-ketone-16 α-alcohol [step D] that is synthesized general formula (II-A) by the compound of general formula (I-A-3)

At room temperature (1.9g, 18mmol) with methylene dichloride (100ml) thorough mixing, (18ml) slowly adds described mixture with tert-butyl peroxide, then at room temperature stirs 1 hour with tin anhydride.This reaction mixture is cooled to 0 ℃, is dissolved with compound (21g, methylene dichloride 70mmol) (100ml) of general formula (I-A-3) with adding in 10 minutes.This mixture heating up to room temperature, and was stirred 2 hours.After reaction is finished,, and extract with ethyl acetate and distilled water through solvent removed by evaporation at reduced pressure.With this organic layer dried over mgso, filter and reduction vaporization, thereby obtain title compound (20g, productive rate: 91%).

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

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

Embodiment 8: the E-guggulusterol [the pregnant diene of 4,17 (20)-E--3-ketone-16 α-alcohol] [step D] that is synthesized general formula (II-A) by the compound of general formula (I-A-3)

With tin anhydride (3.9g, 35mmol) with methylene dichloride (100m1) blended simultaneously, dropwise add tert-butyl peroxide (18ml), then at room temperature stirred 1 hour.This reaction mixture is cooled to 0 ℃, with 10 minutes slow compound (21g, methylene dichloride 70mmol) (100ml) that are dissolved with general formula (I-A-3) that add.This reaction mixture is heated to room temperature, and stirred 1 hour.After reaction is finished,, and extract with ethyl acetate and distilled water through solvent removed by evaporation at reduced pressure.With the organic layer dried over mgso after merging, filter and reduction vaporization, thereby obtain title compound (21g, productive rate: 93%).

Embodiment 9: the E-guggulusterol [the pregnant diene of 4,17 (20)-E--3-ketone-16 α-alcohol] [step D] that is synthesized general formula (II-A) by the compound of general formula (I-A-3)

With tin anhydride (2g, 18mmol) 0 ℃ with dioxane (150ml) blended simultaneously, (6g 50mmol), and stirred 1 hour slowly to add N-methylmorpholine N-oxide compound.Slowly (9g 35mmol), is heated to room temperature with reactant to the compound of adding general formula (I-A-3), and stirs 2 hours.After reaction is finished, the reaction mixture reduction vaporization to dry, is dissolved in ethyl acetate (100ml) with the gained mixture.With salt solution and distilled water wash gained mixture.With the organic layer dried over mgso, filter, and reduction vaporization is as for dry.Adopt ethyl acetate/hexane (v/v=1/1) through the column chromatography purifying this resistates, thereby obtain title compound (22g, productive rate: 82%).

Embodiment 10: by 5,17 (20)-suitable-pregnant diene-3 β-alcohol [step e] of the synthetic general formula (I-B-1) of general formula compound (I-B)

15 ℃ with the ethyl triphenyl phosphonium bromide (130g 350mmol) is dissolved in dried dimethyl sulfoxide (DMSO) (400ml), and slowly add sodium hydride (8.6g, 360mmol).After determining to add, with reaction mixture restir 1 hour, at room temperature in this reaction mixture, add general formula (I-B) DHEA (28.8g, 100mmol).This reactant slowly is heated to 80 ℃, and restir 2 hours.After reaction is finished, reaction mixture is extracted three times with salt solution (800ml) and ethyl acetate (300ml).With the organic layer dried over mgso, filter and reduction vaporization.In the gained resistates, add hexane and ethyl ester (v/v=10/1) (400ml), form by product triphenylphosphine oxide (Ph ₃P=O) throw out filters precipitation is removed, and with filtrate evaporated under reduced pressure, thereby obtains title compound (28.6g, productive rate: 95%).

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

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

Embodiment 11: 5,17 (20)-suitable-pregnant diene-3 β-alcohol [step e] that is synthesized general formula (I-B-1) by the compound of general formula (I-B)

At 15 ℃ with ethyl triphenyl phosphonium bromide (92.8g, 250mmol) be dissolved in dried dimethyl sulfoxide (DMSO) (300ml), slowly add sodium hydride (6.3g again, 260mmol), with this reaction mixture restir 1 hour at room temperature, at room temperature slowly add general formula (I-B) DHEA (28.8g, 100mmol).This reaction mixture slowly is heated to 80 ℃, and restir 2 hours.After reaction is finished, reaction mixture is extracted three times with salt solution (600ml) and ethyl acetate (200ml).With the organic layer dried over mgso after merging, filtration and reduction vaporization are to dry.In the gained mixture, add (300ml) solution of hexane and ethyl ester (v/v=10/1), form by product triphenylphosphine oxide (Ph ₃P=O) throw out filters precipitation is removed.The filtrate reduction vaporization to dry, is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel resistates,, thereby obtain title compound (25.5g, productive rate: 85%) with ethyl acetate/hexane (v/v=3/7) wash-out.

Embodiment 12: 5,17 (20)-suitable-pregnant diene-3 β-alcohol [step e] that is synthesized general formula (I-B-1) by the compound of general formula (I-B)

15 ℃ with the ethyl triphenyl phosphonium bromide (92.8g 250mmol) mixes with the tetrahydrofuran (THF) of doing (300ml), with slow adding in 15 minutes be dissolved with uncle's fourth oxygen potassium dry tetrahydrofuran (1mol) (280ml, 280mmol).After adding, with this reaction mixture restir 1 hour at room temperature, at room temperature slowly add general formula (I-B) DHEA (18.2g, 63mmol).With the slow reflux of this reactant 6 hours.After reaction is finished, removal of solvent under reduced pressure.In mixing solutions, add hexane and ethyl ester (v/v=10/1) (300ml), form by product triphenylphosphine oxide (Ph ₃P=O) throw out filters precipitation is removed.Filtrate evaporated under reduced pressure to dry, is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel resistates,, thereby obtain title compound (15.7g, productive rate: 83%) with ethyl acetate/hexane (v/v=3/7) wash-out.

Embodiment 13: by 5,17 (20)-E-pregnant diene-3 β of the synthetic general formula (II-B) of the compound of general formula (I-B-1), 16 salmefamols [step F]

(5.3g 476mmol) with methylene dichloride (200ml) thorough mixing, slowly adds tert-butyl peroxide (36ml) with tin anhydride at 25 ℃.After 30 minutes, reactant is cooled to 0 ℃, with adding the compound be dissolved with general formula (I-B-1) (28.6g, methylene dichloride 95.2mmol) (100ml), and restir 3.5 hours in 10 minutes.After reaction is finished, the organic layer after merging with salt solution and distilled water wash, is used dried over mgso, filter and reduction vaporization, thereby obtain title compound (27.4g, productive rate: 91%).

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

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

Embodiment 14: by compound 5,17 (20)-E-pregnant diene-3 β of the synthetic general formula (II-B) of the compound of general formula (I-B-1), 16 salmefamols [step F]

(9.2g 83.2mmol) mixes with methylene dichloride (250ml), to wherein slowly adding tert-butyl peroxide (36ml) with tin anhydride at 25 ℃.After 30 minutes, this reaction mixture is cooled to 0 ℃, with 10 minutes slow compound (25g, methylene dichloride 83.2mmol) (100ml) that are dissolved with general formula (I-B-1) that add.Under uniform temp with reaction mixture restir 2 hours.After reaction is finished, organic layer with salt solution and distilled water wash, is used dried over mgso.Reduction vaporization solvent wherein, thus title compound (25.8g, productive rate: 98%) obtained.

Embodiment 15: 5,17 (20)-suitable-pregnant diene-3-ketone [step G] that is synthesized general formula (I-B-2) by the compound of general formula (I-B-1)

0 ℃ of compound with general formula (I-B-1) (25g 83mmol) is dissolved in methylene dichloride (250ml), add then 4 molecular sieves (3g) and pyridinium chlorochromate (PCC, 21.5g, 100mmol).Under uniform temp, reaction mixture was stirred 2 hours, add ether (250ml) and stop this reaction.Remove by product and with gained mixture preliminary purification by quick silicagel column, and filtrate is evaporated to drying.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel,, thereby obtain title compound (22.5g, productive rate: 91%) with ethyl acetate/hexane (v/v=3/7) wash-out.

¹H-NMR (300MHz, CDCl ₃): 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)

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

Embodiment 16: 5,17 (20)-suitable-pregnant diene-3-ketone [step G] that is synthesized general formula (I-B-2) by the compound of general formula (I-B-1)

(5.0g 17mmol) is dissolved in acetone (100ml), slowly adds the Jones reagent (3ml) of 8N then at 10 ℃ of compounds with general formula (I-B-1).Be reflected under the uniform temp and continue 30 minutes, with solvent removed under reduced pressure.Subsequently, the gained mixture is extracted with ethyl acetate and salt solution.With the organic layer dried over mgso, filter and reduction vaporization.With the gained mixture through column chromatography (elutriant: ethyl acetate/hexane solvent=3/7) purify, thereby obtain title compound (3.8g, productive rate: 74%).

Embodiment 17: 4,17 (20)-suitable-pregnant diene-3-ketone [step H] that is synthesized general formula (I-B-3) by the compound of general formula (I-B-2)

At room temperature (22g 73.7mmol) is dissolved in methyl alcohol (100ml), then potassium hydroxide (5g) is dissolved in wherein with the compound of general formula (I-B-2).With reaction mixture reflux 40 minutes, be cooled to room temperature again.Solvent removed by evaporation at reduced pressure, and extract this mixture with ethyl acetate and salt solution.With the organic layer dried over mgso, filter and reduction vaporization, thereby obtain title compound (20g, productive rate: 91%).

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

Embodiment 18: 4,17 (20)-suitable-pregnant diene-3-ketone [step H] that is synthesized general formula (I-B-3) by the compound of general formula (I-B-2)

10 ℃ of compounds with general formula (I-B-2) (15g 50mmol) is dissolved in dried tetrahydrofuran (THF) (80ml), then with slowly added in 15 minutes the tetrahydrofuran (THF) of doing that is dissolved with uncle's fourth oxygen potassium (1M solution, 60ml, 60mmol).Reactant slowly is heated to room temperature, and restir is 1 hour subsequently.Subsequently, remove under reduced pressure and desolvate and to dry, with the gained mixture with ethyl acetate and salt solution extraction.With gained organic layer dried over mgso, filter and reduction vaporization, thereby obtain title compound (14.2g, productive rate: 95%).

Embodiment 19: ring-3-(ethylene the acetal)-5-androstene-17 β-alcohol [step I] that is synthesized general formula (I-C-1) by the compound of general formula (I-C)

25 ℃ with testosterone (I-C, 28.8g 100mmol) are dissolved in benzene (200ml), again to wherein add 1 (6.2ml, 110mmol) and tosic acid (0.2g, 1mmol).With this mixture reflux 3 hours in Dean-Rodney Stark (Dean-Stark) device, to remove moisture.After reaction is finished, this reaction mixture is cooled to room temperature, adds saturated NaHCO again ₃Solution (100ml), with the Separation of Benzene layer, and with ethyl acetate (80ml) extraction three times of remaining water layer.With the organic layer dried over mgso after merging, filter and reduction vaporization.With resistates with silica gel column chromatography (elutriant: ethyl acetate/hexane=3/7) purifying, thereby obtain title compound (25.3g, productive rate: 76%).

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

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

Embodiment 20: ring-3-(ethylene the acetal)-5-androstene-17 β-alcohol [step I] that is synthesized general formula (I-C-1) by the compound of general formula (I-C)

25 ℃ with testosterone (I-C, 28.8g 100mmol) are dissolved in benzene (200ml), again to wherein add 1 (18.6ml, 330mmol) and tosic acid (1g, 5mmol).With this mixture reflux 3 hours in Dean and Stark apparatus, to remove moisture.After reaction is finished, this reaction mixture is cooled to room temperature, adds saturated NaHCO again ₃Solution (100ml), with the Separation of Benzene layer, and with ethyl acetate (80ml) extraction three times of remaining water layer.With the organic layer dried over mgso after merging, filter and reduction vaporization.With resistates with silica gel column chromatography (elutriant: ethyl acetate/hexane=3/7) purifying, thereby obtain title compound (29g, productive rate: 87%).

Embodiment 21: ring-3-(ethylene the dithioacetals)-5-androstene-17-ketone [step J] that is synthesized general formula (I-C-2) by the compound of general formula (I-C-1)

0 ℃ of compound with general formula (I-C-1) (28g 84mmol) is dissolved in methylene dichloride (250ml), again to wherein add 4 molecular sieves (3g) and pyridinium chlorochromate (PCC, 21.5g, 100mmol).With this reaction mixture restir 2 hours under uniform temp, by adding ether (200ml) termination reaction.Make this reaction mixture through flashing tower,, desolvate through evaporating to remove to remove by product.With resistates with silica gel column chromatography (elutriant: ethyl acetate/hexane=3/7) purifying, thereby obtain title compound (23g, productive rate: 83%).

¹H-NMR (300MHz, CDCl ₃): 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)

¹³C-NMR(75.5MHz，CDCl ₃)：221.2，140.7，121.7，109.6，64.8，64.6，52.0，50.1，47.8，42.1，37.1，36.6，36.1，31.8，31.8，31.3，31.0，30.1，22.2，20.7，19.2，13.9

Embodiment 22: ring-3-(ethylene the dithioacetals)-5-androstene-17-ketone [step J] that is synthesized general formula (I-C-2) by the compound of general formula (I-C-1)

0 ℃ of compound with general formula (I-C-1) (28g 84mmol) is dissolved in methylene dichloride (300ml), then to wherein add 4 molecular sieves (5g) and pyridinium chlorochromate (36g, 168mmol).With this reaction mixture restir 2 hours under uniform temp, by adding ether (250ml) termination reaction.Make this reaction mixture through molecular sieve,, desolvate through evaporating to remove to remove by product.With resistates with silica gel column chromatography (elutriant: ethyl acetate/hexane=3/7) purifying, thereby obtain title compound (24.4g, productive rate: 88%).

Embodiment 23: ring-3-(ethylene acetal)-5,17 (20)-suitable-androstene [step K] that is synthesized general formula (I-C-3) by the compound of general formula (I-C-2)

0 ℃ with the ethyl triphenyl phosphonium bromide (37g 100mmol) is dissolved in anhydrous tetrahydro furan (200ml), then with slowly added in 15 minutes the anhydrous tetrahydro furan (1mol solution) that is dissolved with uncle's fourth oxygen potassium (110ml, 110mmol).After adding, reaction mixture was at room temperature reacted 30 minutes again, at room temperature slowly add compound (24g, tetrahydrofuran (THF) 83.2mmol) (150ml) that is dissolved with general formula (I-C-2).With this reaction mixture reflux 2 hours.After reaction is finished, reaction is cooled to room temperature.With this reaction mixture reduction vaporization, so that dry, and (v/v=10/1, mixing solutions 250ml) is with precipitation triphenylphosphine oxide (Ph to pour resistates into hexane and ethyl ester ₃P=O), and after filtration precipitation is removed.With organic layer salt solution and distilled water wash, and use dried over mgso, filter and reduction vaporization.With resistates with silica gel column chromatography (elutriant: ethyl acetate/hexane=1/9) purifying, thereby obtain title compound (23.1g, productive rate: 81%).

¹H-NMR (300MHz, CDCl ₃): 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)

¹³C-NMR(75.5MHz，CDCl ₃)：150.6，140.5，122.5，113.9，109.9，64.9，64.6，56.9，50.1，44.4，42.2，37.4，37.1，36.7，31.8，31.8，31.5，24.9，21.6，19.2，17.0，13.5

Embodiment 24: ring-3-(ethylene acetal)-5,17 (20)-suitable-androstene [step K] that is synthesized general formula (I-C-3) by the compound of general formula (I-C-2)

10 ℃ with the ethyl triphenyl phosphonium bromide (40g 105mmol) is dissolved in anhydrous tetrahydro furan (250ml), slowly add again sodium hydride (2.6g, 110mmol).After adding, this reaction mixture was at room temperature continued to stir 30 minutes, at room temperature slowly add general formula (I-C-2) compound (24g, 83.2mmol).This reaction mixture was at room temperature stirred 2 hours.After reaction is finished, reaction mixture with salt solution (200ml) and ethyl acetate (200ml) washing, is separated organic layer.With the organic layer dried over mgso, filter and reduction vaporization.(v/v=10/1, mixing solutions 250ml) is with precipitation triphenylphosphine oxide (Ph to pour resistates into hexane and ethyl ester ₃P=O), and after filtration precipitation is removed.With filtrate evaporated under reduced pressure, thereby obtain title compound (26.5g, productive rate: 93%).

Embodiment 25: 4,17 (20)-suitable-pregnant diene-3-ketone [step L] that is synthesized general formula (I-A-3) by the compound of general formula (I-C-3)

With the compound of general formula (I-C-3) (26g 76mmol) is dissolved in the acetone (200ml) that contains 5% distilled water, add again the tosic acid pyridine (PPTS, 1.8g, 7mmol).This reaction mixture is heated to 40 ℃, kept 2 hours.After reaction was finished, acetone was removed in decompression, and this reaction mixture is extracted with distilled water (100ml) and ethyl acetate (150ml).With the organic layer dried over mgso, filter and reduction vaporization, thereby obtain title compound (21.3g, productive rate: 94%).

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

Embodiment 26: 4,17 (20)-suitable-pregnant diene-3-ketone [step L] that is synthesized general formula (I-A-3) by the compound of general formula (I-C-3)

(5g 15mmol) mixes with 75% Glacial acetic acid (45ml), with mixture heating up to 60 ℃, keeps 30 minutes then with the compound of general formula (I-C-3).After reaction is finished, reaction mixture is cooled to room temperature, with salt solution (30ml) and ethyl acetate (50ml * 3) extractive reaction mixture.By adding saturated NaHCO ₃The aqueous solution and distilled water are removed Glacial acetic acid remaining in the organic layer, with the organic layer dried over mgso, filter, and solvent evaporated under reduced pressure is so that dry.With gained resistates column chromatography (elutriant: ethyl acetate/hexane=3/7) purify, thereby obtain title compound (3.8g, productive rate: 84%).

Embodiment 27: by 5,17 (20)-E-pregnant diene-3 β of the synthetic general formula (II-B) of the compound of general formula (I-D), 16 salmefamols [step M]

At room temperature with the compound of general formula (I-D) (33.1g, 100mmol) and potassium hydroxide (50g) be dissolved in glycol ether (200ml), (97ml 2mol) adds wherein with the hydrazine monohydrate again.This reaction mixture is heated to 120 ℃ refluxed 1 hour, remove condenser after, be reflected at 160 ℃ and carried out again 2 hours.After confirming that by TLC (tlc) reaction is finished, this reaction is cooled to room temperature.This reaction mixture is mixed with distilled water (200ml), use chloroform (200ml) extraction three times again.With the organic layer dried over mgso, filter, and solvent removed by evaporation at reduced pressure, thereby obtain title compound (28.8g, productive rate: 91%).

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

Embodiment 28: by the 4-pregnene-3 of the synthetic general formula (I-E-1) of the compound of general formula (I-E), 20-glycol [step N]

(31.5g 100mmol) is dissolved in methyl alcohol (300ml), adds sodium borohydride (NaBH then carefully at 0 ℃ of progesterone with general formula (I-E) ₄, 7.6g, 200mmol).Be reflected at 20 ℃ and carried out 2 hours, through solvent removed by evaporation at reduced pressure.Extract this reaction mixture with ethyl acetate and salt solution,, filter and reduction vaporization, thereby obtain title compound (31.2g, productive rate: 98%) then with the organic layer dried over mgso.

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

¹³C?NMR(75.5MHz，CDCl ₃)：148.0，123.8，70.9，68.3，59.0，56.1，54.9，42.8，40.4，37.8，36.3，35.8，33.6，32.6，29.9，26.0，24.9，24.0，21.3，19.3，12-8

Embodiment 29: by the 4-pregnene-3 of the synthetic general formula (I-E-1) of the compound of general formula (I-E), 20-glycol [step N]

(31.5g 100mmol) is dissolved in anhydrous methylene chloride (300ml), adds the hexane (220ml) that is dissolved with 1.0M diisobutyl aluminium hydride (DIBAL-H) then carefully at-78 ℃ of progesterone with general formula (I-E).After this is reflected at and carries out 2 hours under the uniform temp, reactant is heated to-20 ℃, and adds ethyl acetate (5ml), restir is 20 minutes subsequently.Reactant is heated to 0 ℃, removes too much reductive agent through slowly adding distilled water (1ml) then.Organic layer is extracted with 10% sulfuric acid, use distilled water wash again, use dried over mgso.It is filtered and reduction vaporization, thereby obtain title compound (30.6g, productive rate: 96%).

Embodiment 30: the 20-hydroxyl-4-by the synthetic general formula (I-E-2) of the compound of general formula (I-E-1) is pregnant-and 3-ketone [step O]

At room temperature with the compound of general formula (I-E-1) (30g 94mmol) is dissolved in methylene dichloride (300ml), add immediately then activity oxidation manganese (81g, 940mmol).This reactant is heated to 40 ℃, and vigorous stirring 2 hours.After reaction is finished, make reaction mixture pass through quick silicagel column, to remove manganese oxide.Through solvent removed by evaporation at reduced pressure, thereby obtain title compound (27.4g, productive rate: 92%).

¹H-NMR (300MHz, CDCl ₃): 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)

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

Embodiment 31: the 20-hydroxyl-4-by the synthetic general formula (I-E-2) of the compound of general formula (I-E-1) is pregnant-and 3-ketone [step O]

At room temperature with the compound of general formula (I-E-1) (30g 94mmol) is dissolved in methylene dichloride (300ml), add immediately then activity oxidation manganese (163g, 1.88mol).This reactant is heated to 40 ℃, and vigorous stirring 1 hour.After reaction is finished, make reaction mixture pass through quick silicagel column, to remove manganese oxide.Through solvent removed by evaporation at reduced pressure, thereby obtain title compound (28.6g, productive rate: 96%).

Embodiment 32: 20-(the p-toluenesulfonyl)-4-by the synthetic general formula (I-E-3) of the compound of general formula (I-E-2) is pregnant-and 3-ketone [step P]

0 ℃ of compound with general formula (I-E-2) (28g, 88.5mmol) and N, the N-dimethyl aminopyridine (DMAP, 21.6g 177mmol) are dissolved in anhydrous methylene chloride (350ml), slowly add then Tosyl chloride (TsCl, 25.3g, 133mmol).Reaction is heated to room temperature, and stirred 4 hours.After TLC confirms that reaction is finished, with aqueous ammonium chloride solution (150ml) extraction organic layer.With the organic layer dried over mgso, filter and reduction vaporization, thereby obtain title compound (35.8g, productive rate: 86%).

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

¹³C?NMR(75.5MHz，CDCl ₃)：200.0，171.2，144.7，130.1，130.1，127.9，126.9，124.2，82.6，56.0，55.7，54.1，42.6，39.0，38.6，36.1，35.9，34.4，33.2，32.4，25.8，24.4，22.0，21.9，21.2，20.9，17.8，12.2

Embodiment 33: 20-(the methylsulfonyl)-4-by the synthetic general formula (I-E-3) of general formula (I-E-2) compound is pregnant-and 3-ketone [step P]

0 ℃ of compound with general formula (I-E-2) (28g, 88.5mmol) and triethylamine (TEA) (17ml 124mmol) is dissolved in anhydrous methylene chloride (250ml), and slowly add Methanesulfonyl chloride (MsCl, 8.2ml, 106mmol).This reaction mixture is heated to room temperature, and reaction continues 4 hours.After reaction is finished, with aqueous ammonium chloride solution (NH ₄Cl) (100ml) extraction organic layer.With the organic layer dried over mgso, filter and reduction vaporization, thereby obtain title compound (33.2g, productive rate: 95%).

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

Embodiment 34: the suitable back mixing compound [step Q] that is synthesized 4,17 (20)-pregnant diene-3-ketone of general formula (I-E-4) by the compound of general formula (I-E-3)

At room temperature (Ots, 35g 74mmol) are dissolved in pyridine (100ml) with the compound of general formula (I-E-3).Reaction mixture is heated to 120 ℃ to reflux 3 hours.After reaction was finished, pyridine solvent was removed in decompression.The gained resistates is dissolved in ethyl acetate (150ml), with 1N HCl solution washing.With the organic layer dried over mgso, filter and reduction vaporization, thereby obtain title compound (21.4g, productive rate: 97%).

¹³C?NMR(75.5MHz，CDCl ₃)：199.9，171.7，150.0，124.21，114.1，56.0，54.2，44.5，39.0，37.2，36.1，35.5，34.4，33.3，32.3，31.7，24.8，21.6，17.7，17-2，13.5

Embodiment 35: the cis-trans-isomer mixture [step Q] that is synthesized 4,17 (20)-pregnant diene-3-ketone of general formula (I-E-4) by the compound of general formula (I-E-3)

At room temperature (Ots, 17.5g 37mmol) are dissolved in anhydrous methanol (80ml) with the compound of general formula (I-E-3).In above-mentioned solution, add sodium methoxide (6g, 111mmol), with this reaction mixture reflux 4 hours.After reaction is finished, removal of solvent under reduced pressure.Reaction mixture is dissolved in ethyl acetate (100ml), and uses the salt water washing.With the organic layer dried over mgso, filter and reduction vaporization, thereby obtain title compound (10.1g, productive rate: 91%).

Embodiment 36: the cis-trans-isomer mixture [step Q] that is synthesized 4,17 (20)-pregnant diene-3-ketone of general formula (I-E-4) by the compound of general formula (I-E-3)

At room temperature (Oms, 20g 51mmol) are dissolved in pyridine (80ml) with the compound of general formula (I-E-3).This reaction mixture is heated to 120 ℃, refluxed 2 hours.After reaction was finished, pyridine solvent was removed in decompression.The gained reaction mixture is dissolved in ethyl acetate (100ml), and with 1N HCl solution washing.With the organic layer dried over mgso, filter and reduction vaporization, thereby obtain title compound (14.5g, productive rate: 95%).

Embodiment 37: the cis-trans-isomer mixture [step Q] that is synthesized 4,17 (20)-pregnant diene-3-ketone of general formula (I-E-4) by the compound of general formula (I-E-3)

At room temperature (Ots, 10g 25.5mmol) are dissolved in anhydrous methanol (80ml) with the compound of general formula (I-E-3).In above-mentioned solution, add sodium methoxide (5.5g, 102mmol), with this reaction mixture reflux 4 hours.After reaction is finished, removal of solvent under reduced pressure.The gained resistates is dissolved in ethyl acetate (100ml), and uses the salt water washing.With the organic layer dried over mgso, filter and reduction vaporization, thereby obtain title compound (7.1g, productive rate: 93%).

Embodiment 38: the E-myrrh sterone [4,17 (20)-E-pregnant diene-3,16-diketone] [step R] that is synthesized general formula (III) by the compound of general formula (II-A)

At room temperature (22g 70mmol) is dissolved in methylene dichloride (200ml) with the E-guggulusterol of general formula (II-A).In above-mentioned solution, add activated manganese dioxide (MnO immediately ₂, 60g, 700mmol), vigorous stirring is 2 hours then.After reaction is finished, remove unnecessary Manganse Dioxide after filtration.Solvent removed by evaporation at reduced pressure, thus title compound (20.6g, productive rate: 94%) obtained.

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

¹³C?NMR(75.5MHz，CDCl ₃)：206，199.6，170.5，147.8，129.9，124.5，53.8，49.9，43.5，39.0，38.2，36.4，35.9，34.7，34.3，32.9，32.2，21.1，17.9，17.7，13.6

Embodiment 39: the E-myrrh sterone [4,17 (20)-E-pregnant diene-3,16-diketone] [step R] that is synthesized general formula (III) by the compound of general formula (II-A)

At room temperature (22g 70mmol) is dissolved in methylene dichloride (300ml) with the E-guggulusterol of general formula (II-A).In above-mentioned solution, add activated manganese dioxide (MnO immediately ₂, 120g, 1.4mol), and vigorous stirring 1 hour.After reaction is finished, remove unnecessary Manganse Dioxide after filtration.Solvent removed by evaporation at reduced pressure, thus title compound (21.4g, productive rate: 98%) obtained.

Embodiment 40: the E-myrrh sterone [4,17 (20)-E-pregnant diene-3,16-diketone] [step S] that is synthesized general formula (III) by the compound of general formula (II-B)

At room temperature (25g 79mmol) is dissolved in benzene (200ml) with the compound of general formula (II-B).In above-mentioned solution order add pimelinketone (82ml) and aluminum isopropoxide (8.1g, 40mmol).With reaction mixture 80 ℃ of reflux 2 hours.After said mixture is cooled to room temperature, add 10% aqueous sulfuric acid (50ml), then vigorous stirring 15 minutes at room temperature.The Separation of Benzene layer, (150ml) extracts remaining water layer with ethyl acetate.With the organic layer dried over mgso after merging, filter also reduction vaporization, thereby obtain title compound (22.8g, productive rate: 92%, single E-myrrh sterone).

¹H-NMR (300MHz, CDCl3): 6.52 (q, 1H), 5.76 (s, 1H), 2.50-1.08 (steroid main body and 1.89 (d, 3H), 1.25 (s, 3H), 1.08 (s, 3H)=26H)

¹³C-NMR(75.5MHz，CDCl3)：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

Embodiment 41: the E-myrrh sterone [4,17 (20)-E-pregnant diene-3,16-diketone] [step S] that is synthesized general formula (III) by the compound of general formula (II-B)

At room temperature (25g 79mmol) is dissolved in toluene (200ml) with the compound of general formula (II-B).In above-mentioned solution order add pimelinketone (82ml) and aluminum isopropoxide (8.1g, 40mmol).Reaction mixture is heated to 120 ℃, refluxed 2 hours.After said mixture is cooled to room temperature, add 10% aqueous sulfuric acid (50ml), then vigorous stirring 15 minutes at room temperature.The Separation of Benzene layer, (150ml) extracts remaining water layer with ethyl acetate.With the organic layer dried over mgso after merging, filter also reduction vaporization, thereby obtain title compound (23.3g, productive rate: 94%, E: Z=7: 3 myrrh sterone).

Embodiment 42: the E-myrrh sterone [4,17 (20)-E-pregnant diene-3,16-diketone] [step S] that is synthesized general formula (III) by the compound of general formula (II-B)

At room temperature (25g 79mmol) is dissolved in toluene (200ml) with the compound of general formula (II-B).In above-mentioned solution order add pimelinketone (82ml) and tri sec-butoxy aluminum (10g, 40mmol).Reaction mixture is heated to 120 ℃, refluxed 2 hours.After said mixture is cooled to room temperature, add 10% aqueous sulfuric acid (50ml), then vigorous stirring 15 minutes at room temperature.The Separation of Benzene layer, (150ml) extracts remaining water layer with ethyl acetate.With the organic layer dried over mgso after merging, filter also reduction vaporization, thereby obtain title compound (22.5g, productive rate: 91%, E: Z=3: 1 myrrh sterone).

Embodiment 43: the E-myrrh sterone [4,17 (20)-E-pregnant diene-3,16-diketone] [step S] that is synthesized general formula (III) by the compound of general formula (II-B)

At room temperature (8.3g 26mmol) is dissolved in benzene (100ml) with the compound of general formula (II-B).In above-mentioned solution, add successively methylethylketone (60ml) and aluminum isopropoxide (3g, 13mmol).Reaction mixture is heated to 80 ℃, refluxed 4 hours.After said mixture is cooled to room temperature, add 10% aqueous sulfuric acid (15ml), then vigorous stirring 15 minutes at room temperature.The Separation of Benzene layer, (50ml) extracts remaining water layer with ethyl acetate.With the organic layer dried over mgso after merging, filter also reduction vaporization, thereby obtain title compound (2.6g, productive rate: 32%, single E-myrrh sterone).

Embodiment 44: the Z-myrrh sterone [4,17 (20)-Z-pregnant diene-3,16-diketone] [step T] that is synthesized general formula (IV) by the compound of general formula (III)

At room temperature (1g 3.2mmol) is dissolved in methylene dichloride (20ml), then methylenum coeruleum (5mg) is dissolved in wherein with the E-myrrh sterone of general formula (III).Reaction mixture is cooled to 0 ℃, uses the tungsten lamp of 300W to shine 6 hours.The gained mixture is passed through quick silicagel column, through solvent removed by evaporation at reduced pressure.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel,, thereby obtain title compound (433mg, productive rate: 43.3%), reclaim unreacted E-myrrh sterone (560mg) with ethyl acetate/hexane (v/v=3/7) wash-out.

¹H-NMR (300MHz, CDCl ₃): 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)

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

Embodiment 45: the Z-myrrh sterone [4,17 (20)-Z-pregnant diene-3,16-diketone] [step T] that is synthesized general formula (IV) by the compound of general formula (III)

At room temperature (1g 3.2mmol) is dissolved in toluene (100ml) with the E-myrrh sterone of general formula (III).With the nitrogen purging reaction unit and with its complete closed.Be reflected at 160 ℃ and continue 2 hours, be cooled to room temperature again.Removal of solvent under reduced pressure.The gained mixture is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel,, thereby obtain title compound (586mg, productive rate: 58.6%), reclaim unreacted E-myrrh sterone (410mg) with ethyl acetate/hexane (v/v=3/7) wash-out.

Embodiment 46: the Z-myrrh sterone [4,17 (20)-Z-pregnant diene-3,16-diketone] [step T] that is synthesized general formula (IV) by the compound of general formula (III)

At room temperature (1g 3.2mmol) is dissolved in the benzene (100ml) that contains tosic acid (100mg) with the E-myrrh sterone of general formula (III).Reaction mixture is heated to 80 ℃, refluxed 1 hour, be cooled to room temperature then, again reduction vaporization.The gained mixture is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel,, thereby obtain title compound (664mg, productive rate: 64.4%), reclaim unreacted E-myrrh sterone (350mg) with ethyl acetate/hexane (v/v=3/7) wash-out.

Industrial applicibility

According to the present invention, can low-cost high productivity prepare the pregnant diene of 4,17 (20)-E-of general formula (III) 4,17 (20)-Z-pregnant two of-3,16-diketone (E-myrrh sterone) and enantiomter and general formula (IV) Alkene-3,16-diketone (Z-myrrh sterone), their effect is effectively to reduce high low-density lipoprotein In vain (LDL) level and high cholesterol levels, and improve low hdl level.

Claims

1. one kind prepares 4 of following general formula (IV), 17 (20)-Z-pregnant diene-3, the method of 16-diketone, this method comprise, the compound oxidation of following general formula (II) is obtained 4 of following general formula (III), 17 (20)-E-pregnant diene-3, the 16-diketone makes 4,17 (20)-E-pregnant diene-3 of the above-mentioned general formula (III) of gained, the 16-diketone is selected from any reaction in the group of being made up of photochemical reaction, thermal chemical reaction and acid catalyzed reaction

Wherein, C represent hydroxy (OH) or the oxygen base (=O), dotted line is illustrated on C-4 or the C-5 position two keys.

2. the method for claim 1, wherein carry out described photochemical reaction by being selected from by the photosensitizers in methylenum coeruleum, methylene green and the rose-red group of forming.

3. the method for claim 1, wherein by solvent benzene,toluene,xylene or 1 were carried out described thermal chemical reaction in 1 hour to 48 hours 80 ℃～200 ℃ reflux.

4. the method for claim 1, wherein described an acidic catalyst is a tosic acid.

5. the method for the compound of preparation general formula as claimed in claim 1 (II); this method comprises; with 1; the 2-dithioglycol is protected the compound of general formula (I-A), thereby obtains the compound of general formula (I-A-1), makes the compound of the general formula (I-A-1) of gained carry out Wittig reaction; obtain the compound of general formula (I-A-2); remove blocking group, obtain the compound of general formula (I-A-3), make gained compound and tin anhydride (SeO ₂) reaction.

6. the method for the compound of preparation general formula as claimed in claim 1 (II), this method comprise makes the compound of general formula (I-B) carry out Wittig reaction, obtains the compound of general formula (I-B-1), makes the compound and the tin anhydride (SeO of gained general formula (I-B-1) ₂) reaction.

7. the method for the compound of preparation general formula as claimed in claim 1 (II), this method comprises, make the compound of general formula (I-B) carry out Wittig reaction, obtain the compound of general formula (I-B-1), with pyridinium chlorochromate (PCC) oxidation gained compound, obtain the compound of general formula (I-B-2), the gained compound is reacted in the presence of alkali, obtain the compound of general formula (I-B-3), make the reaction of products therefrom and tin anhydride.

8. the method for the compound of preparation general formula as claimed in claim 1 (II); this method comprises; with 1; the 2-dithioglycol is protected the compound of general formula (I-C) in the presence of an acidic catalyst, obtain the compound of general formula (I-C-1), makes the gained compound carry out Wittig reaction with ethyl triphenyl phosphonium halide in the presence of highly basic; obtain the compound of general formula (I-C-3); the ketone group of the compound of general formula (I-C-3) is gone protection, obtain the compound of general formula (I-A-3), with tin anhydride (SeO ₂) the oxidation products therefrom.

9. the method for the compound of preparation general formula as claimed in claim 1 (II), this method comprise, and in the presence of alkali, make the compound and the hydrazine reaction of general formula (I-D).

10. the method for the compound of preparation general formula as claimed in claim 1 (II); this method comprises; the compound of reduction general formula (I-E); obtain the compound of general formula (I-E-1); apparatus oxygenant oxidation selectively gained compound; obtain the compound of general formula (I-E-2); introduce p-toluenesulfonyl or methylsulfonyl for the compound of gained general formula (1-E-2); obtain the compound of general formula (I-E-3); make this product and alkali reaction; obtain the compound of general formula (I-E-4), make the compound and the tin anhydride (SeO of general formula (I-E-4) ₂) reaction.