CN101735300B - Method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol - Google Patents
Method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol Download PDFInfo
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Abstract
The invention discloses a method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol, comprising the following steps of: preparing steride-4,6-dien-3beta-ol by using steride-4,6-dien-3beta-one as the raw material through a reductive reaction; preparing 4beta,5beta-epoxy steride-6-alkenyl-3beta-ol by the steride-4,6-dien-3beta-ol through epoxidation; preparing the intermediate steride-6-alkenyl-3beta,5beta-diol by the 4beta,5beta-epoxy steride-6-alkenyl-3beta-ol through a reductive ring opening reaction, and preparing the aimed compound 6beta,7beta-methylene-steride-3beta,5beta-diol by the intermediate through cyclopropanation reaction addition or directly preparing the aimed compound 6beta,7beta-methylene-steride-3beta,5beta-diol by the 4beta,5beta-epoxy steride-6-alkenyl-3beta-ol through cyclopropanation reaction. The invention has the advantages of low cost and easy availability of raw material, easy preparation of 4beta,5beta-epoxy steride-6-alkenyl-3beta-ol, high stereoselectivity for constructing 6beta,7beta-methylene structural unit, less reaction steps, simple operation and high yield, therefore, the method is suitable for industrialized production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry synthesis technical field, especially relate to a kind of 6 β, 7 β-methylene radical-steroidal-3 β, the preparation method of 5 beta-diols.
Background technology
6 β, 7 β-methylene radical-steroidal-3 β, 5 beta-diols are synthetic a kind of novel steroid progestogen drospirenone (Drospirenone, key intermediates Drospirenone).6 β, the classical chemical process of the structure of 7 β-methylene radical structural unit all is to adopt the Δ of conjugated diene compound
6The Micheal addition takes place and obtains in-alkene position and Corey methylenation reagent; Perhaps using the Zn-Cu/ methylene halide to carry out the Simmons-Smith addition reaction realizes.The Simmons-Smith addition that was improved to afterwards through 5 beta-hydroxy positioning and guidings realizes that its stereoselectivity and productive rate all significantly improve.But introduce 5 beta-hydroxies-Δ
6-alkene structural unit must be through radical protection, allylic oxidation, selective reduction, 5 β, and reactions such as 6 beta epoxideizations, halo and cancellation obtain; Employing makes with the similar reaction of above-mentioned chemical process after perhaps introducing the 7-hydroxyl with microbial fermentation processes.No matter pure chemistry compound method or fermentative routes, its reactions step is tediously long, and reagent is expensive, and overall yield is low, and environmental protection cost is high.CN101177446A has reported that a kind of Winstein of utilization Cyclopropanation process stereoselectivity synthesizes 6 β; The novel method of 7 β-methylene radical structure; But this method still needs 7-position allylic oxidation, and reaction reagent is expensive, reactions step is long, total recovery is on the low side etc.
Therefore, develop a kind of 6 β of simple and effective, the construction process meaning of 7 β-methylene radical structure is very great.
Summary of the invention
Technical problem to be solved by this invention is a kind of 6 β to be provided, 7 β-methylene radical-steroidal-3 β to above-mentioned deficiency of the prior art; The preparation method of 5 beta-diols, this method low in raw material cost is easy to get, midbody 4 β; 5 beta epoxides steroidal-6-alkene-3 β-alcohol is easy to preparation, makes up 6 β, and the stereoselectivity of 7 β-methylene radical structural unit is high; Reactions step is few, and is simple to operate high with yield, is fit to suitability for industrialized production.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is: a kind of 6 β, and 7 β-methylene radical-steroidal-3 β, the preparation method of 5 beta-diols is characterized in that this method may further comprise the steps:
Step 1, be raw material, prepare compound 3 (steroidal-4,6-diene-3 β-alcohol) through reduction reaction with compound 2 (steroidal-4,6-diene-3-ketone);
Step 2, the compound in the step 13 (steroidal-4,6-diene-3 β-alcohol) is made compound 4 (4 β, 5 beta epoxides steroidal-6-alkene-3 β-alcohol) through epoxidation reaction;
Step 3, the compound in the step 24 (4 β, 5 beta epoxides steroidal-6-alkene-3 β-alcohol) is made midbody 5 (steroidal-6-alkene-3 β, 5 beta-diols) through reductive ring open reaction; Midbody 5 (steroidal-6-alkene-3 β; 5 beta-diols) make target compound 1 (6 β, 7 β-methylene radical-steroidal-3 β, 5 beta-diols) through cyclopropanization reaction; Perhaps by compound 4 (4 β; 5 beta epoxides steroidal-6-alkene-3 β-alcohol) directly makes target compound 1 (6 β, 7 β-methylene radical-steroidal-3 β, 5 beta-diols) through cyclopropanization reaction;
In the formula:
The reductive agent that adopts in the reduction reaction described in the step 1 is a Peng Qinghuana; Sodium cyanoborohydride; POTASSIUM BOROHYDRIDE 97MIN; Lithium borohydride; Zinc borohydride; Three-methoxyl group Peng Qinghuana; Three-ethyl lithium borohydride; Three-sec.-butyl lithium borohydride; Three-sec.-butyl POTASSIUM BOROHYDRIDE 97MIN; Three-isopropoxy POTASSIUM BOROHYDRIDE 97MIN; Aluminium lithium hydrogen; Three-tertiary butyl aluminium lithium hydrogen; The Di-Isobutyl aluminum hydride; Diborane; The tetrahydrofuran solution of borine; The dimethyl sulphide solution of borine; Aluminium alkane; Raney Ni; Samarium diodide; Triethyl silicon hydrogen or zinc powder.
The reaction solvent that adopts in the said reduction reaction is methyl alcohol, ethanol, Virahol, acetone, chloroform, 1,4-dioxane, ETHYLE ACETATE, acetonitrile, ether, benzene, pyridine, THF, methylene dichloride, DMF or DMSO; Temperature of reaction in the reduction reaction is 0 ℃~70 ℃, preferred 0 ℃~35 ℃.
Said reductive agent consumption is 1~10 times of molar equivalent of compound 2 (steroidal-4,6-diene-3-ketone), preferred 1~3 times of molar equivalent.
The epoxidation reagent that adopts in the epoxidation reaction described in the above-mentioned steps two is metachloroperbenzoic acid, Peracetic Acid, tertbutyl peroxide/VO (acac)
2System, potassium permanganate/nitrate salt system, trifluoroacetone/Oxone system or bisoxirane, preferred metachloroperbenzoic acid, Peracetic Acid or tertbutyl peroxide.
The reaction solvent that adopts in the said epoxidation reaction is toluene, benzene, acetone, acetonitrile, methylene dichloride or DMSO, preferred toluene or methylene dichloride; Temperature of reaction in the said epoxidation reaction is 0 ℃~70 ℃, preferred 0 ℃~35 ℃.
Said epoxidation reagent consumption is 1~10 times of molar equivalent of compound 3 (steroidal-4,6-diene-3 β-alcohol), preferred 1~3 times of molar equivalent.
The reductive ring open reagent that adopts in the reaction of reductive ring open described in the above-mentioned steps three is Peng Qinghuana; Sodium cyanoborohydride; POTASSIUM BOROHYDRIDE 97MIN; Lithium borohydride; Zinc borohydride; Three-methoxyl group Peng Qinghuana; Three-ethyl lithium borohydride; Three-sec.-butyl lithium borohydride; Three-sec.-butyl POTASSIUM BOROHYDRIDE 97MIN; Three-isopropoxy POTASSIUM BOROHYDRIDE 97MIN; Lithium aluminum hydride; Three-tertiary butyl aluminium lithium hydrogen; The Di-Isobutyl aluminum hydride; Diborane; The tetrahydrofuran solution of borine; The dimethyl sulphide solution of borine; Aluminium alkane; Raney Ni; Samarium diodide; Triethyl silicon hydrogen; Zinc ethyl or zinc powder; Preferred lithium aluminum hydride, zinc powder or Peng Qinghuana.
The reductive ring open reaction solvent that adopts in the said reductive ring open reaction is methyl alcohol, ethanol, Virahol, acetone, chloroform, 1,4-dioxane, ETHYLE ACETATE, acetonitrile, ether, benzene, pyridine, THF, methylene dichloride, THF, DMF or DMSO; Preferred toluene, methylene dichloride or THF.
Temperature of reaction in the said reductive ring open reaction is-10 ℃~90 ℃, preferred 0 ℃~35 ℃.
Said reductive ring open reagent dosage is 1~10 times of molar equivalent of compound 4 (4 β, 5 beta epoxides steroidal-6-alkene-3 β-alcohol), preferred 1~3 times of molar equivalent.
The cyclopropanation reagents that cyclopropanization reaction described in the above-mentioned steps three adopts is methylene iodide, methylene bromide or sulfur ylide, and employed initiator is an iodine, and employed catalyzer is Zn-Cu powder or zinc ethyl, preferred Zn-Cu powder; Employed reaction solvent is methyl glycol, glycol dimethyl ether, 1,4-dioxane, DMSO or THF, preferred glycol dimethyl ether or DMSO; Temperature of reaction is 0 ℃~90 ℃, preferred 10 ℃~80 ℃; Said cyclopropanation reagents consumption is 1~10 times of molar equivalent of compound 4, preferred 1~3 times of molar equivalent.
The present invention compared with prior art has the following advantages: advantage of the present invention is that low in raw material cost is easy to get; Compound 4 β, 5 beta epoxides steroidal-6-alkene-3 β-alcohol are easy to preparation, make up 6 β; The stereoselectivity of 7 β-methylene radical structural unit is high; Reactions step is few, and is simple to operate high with yield, is fit to suitability for industrialized production.
Through embodiment, technical scheme of the present invention is done further detailed description below.
Embodiment
Embodiment 1
Under room temperature, to being dissolved with Δ
4,6-male diene-3, the 17-diketone (1.0g, (537mg, 14.2mmol), spend the night to add Peng Qinghuana in absolute ethyl alcohol 3.5mmol) (100mL) solution by insulated and stirred.The reaction final vacuum extracting that finishes removes solvent and gets white solid.This white solid is placed water, stir 30min.Use dichloromethane extraction (3 * 100mL) then.Organic layer is used sodium bicarbonate aqueous solution, water washing successively, and anhydrous magnesium sulfate drying filters, and concentrates, and ETHYLE ACETATE/normal hexane (1: 2) recrystallization obtains Δ after the vacuum-drying
4,6-male diene-3 β, 17-isoallopregnane-3, white crystals, 630mg (63%, 2.2mmol); Mp:155~158 ℃; IR (cm-1): 3400,2960,1670,1460;
1H-NMR δ: 3.62~3.66 (1H, m, H-3), 5.60 (1H, d, J=9.8Hz, H-6), 5.96 (1H, dd, J=2.4Hz, 10.0Hz, H-7).
Embodiment 2
Under room temperature, (m-CPBA, 600mg 3.5mmol) add Δ with metachloroperbenzoic acid
4,6-male diene-3 β, 17-isoallopregnane-3 (500mg, in methylene dichloride 1.7mmol) (50mL) solution, spend the night by insulated and stirred.React the Hou Jiashui (50mL) that finishes, stir 30min.Divide water-yielding stratum, use dichloromethane extraction (3 * 50mL) water layers then.Merge organic layer, use sodium sulfite aqueous solution (10%), sodium bicarbonate aqueous solution, water and brine wash successively, anhydrous magnesium sulfate drying; Filter, concentrate, post separates or with ETHYLE ACETATE/normal hexane (1: 2) recrystallization; Obtain 4 β after the vacuum-drying, 5 beta epoxides-Δ
6-Cetadiol, 17-isoallopregnane-3, white crystals, 332mg (65%, 1.1mmol); Mp:146~148 ℃; IR (cm
-1): 3405,2933,1455;
1H-NMR δ: 3.57~3.80 (2H, m, H-3, H-17), 4.17 (1H, d, J=3.2Hz, H-4), 5.32 (1H, dd, J=2.2Hz, 6.4Hz, H-7), 5.64 (1H, d, J=2.2Hz, H-6).
Embodiment 3
With 4 β, 5 beta epoxides-Δ
6-Cetadiol, (10.5g 34.5mmol) adds anhydrous tetrahydro furan (300mL)/LiAlH to 17-isoallopregnane-3
4(5.7g is in suspension-s 150mmol).Stirring at room reaction is up to reaction finish (TLC follows the tracks of reaction, needs 40min approximately).To react feed liquid and place on the ice-water bath, and continue to stir, and dropwise drip methyl alcohol and emit, and then stir adding 10% aqueous hydrochloric acid (1000mL) up to no gas.(3 * 100mL) extract, and after the ether layer was used water washing, anhydrous magnesium sulfate drying successively, vacuum extraction was removed and desolvated, and the ether recrystallization filters, and vacuum-drying obtains Δ with isopropyl ether
6-Cetadiol, 5 β, 17 beta-triols, white crystalline powder, 9.8g (93%, 32.1mmol); Mp:110~113 ℃.
Embodiment 4
With Δ
6-Cetadiol, 5 β, (26g 84.8mmol) is dissolved in the glycol dimethyl ether (520mL) 17 beta-triols, stirs, and adds Zn-Cu preparation (78g), methylene iodide (69mL).Be warming up to 75 ℃~80 ℃, insulation reaction 4h.After reaction finishes, be cooled to room temperature, add methylene dichloride (500mL) dilution, use saturated aqueous ammonium chloride, water washing successively; Anhydrous magnesium sulfate drying, vacuum extraction is removed and is desolvated recrystallization, vacuum-drying; Obtain target compound 6 β, 7 β-methylene radical-androstane-3 β, 5 β, 17 beta-triols; White solid, and 16.3g (63%, 50.9mmol); Mp:205~207 ℃.
Embodiment 5
Under room temperature, to being dissolved with 3-oxo-17 α-pregnant steroid-4,6-diene-21,17-carboxylic lactone (1g, (133mg, 3.5mmol), spend the night to add Peng Qinghuana in absolute ethyl alcohol 2.9mmol) (100mL) solution by insulated and stirred.The reaction final vacuum extracting that finishes removes solvent and gets white solid.This white solid is placed water, stir 30min.Use dichloromethane extraction (3 * 100mL) then.Organic layer is used sodium bicarbonate aqueous solution, water washing successively, and anhydrous magnesium sulfate drying filters, and concentrates; ETHYLE ACETATE/normal hexane (1: 2) recrystallization obtains 17 α-pregnant steroid-4 after the vacuum-drying, 6-diene-3 β-alcohol-21; 17-carboxylic lactone, white crystals 730mg (2.1mmol, 73%).
Embodiment 6
Under room temperature, with metachloroperbenzoic acid (m-CPBA, 600mg 3.5mmol) add 17 α-pregnant steroid-4,6-diene-3 β-alcohol-21,17-carboxylic lactone (500mg, in methylene dichloride 1.5mmol) (50mL) solution, spend the night by insulated and stirred.React the Hou Jiashui (50mL) that finishes, stir 30min.Divide water-yielding stratum, use dichloromethane extraction (3 * 50mL) water layers then.Merge organic layer, use sodium sulfite aqueous solution (10%), sodium bicarbonate aqueous solution, water and brine wash successively, anhydrous magnesium sulfate drying; Filter, concentrate, post separates or with ETHYLE ACETATE/normal hexane (1: 2) recrystallization; Obtain 4 β after the vacuum-drying, 5 beta epoxides-17 α-pregnant steroid-6-alkene-3 β-alcohol-21,17-carboxylic lactone; The off-white color crystallization, 360mg (1.0mmol, 67%).
Embodiment 7
With 4 β, 5 beta epoxides-17 α-pregnant steroid-6-alkene-3 β-alcohol-21, (1.1g 3.1mmol) adds anhydrous tetrahydro furan (150mL)/LiAlH to 17-carboxylic lactone
4(570mg is in suspension-s 15.0mmol).Stirring at room reaction is up to reaction finish (TLC follows the tracks of reaction, needs 40min approximately).To react feed liquid and place on the ice-water bath, and continue to stir, and dropwise drip methyl alcohol and emit, and then stir adding 10% aqueous hydrochloric acid (200mL) up to no gas.(3 * 50mL) extract, and after the ether layer was used water washing, anhydrous magnesium sulfate drying successively, vacuum extraction was removed and desolvated with isopropyl ether; The ether recrystallization filters vacuum-drying; Obtain compound 17 α-pregnant steroid-6-alkene-3 β, 5 beta-diols-21,17-carboxylic lactone; White crystalline powder, 1.0g (2.8mmol, 90%).
Embodiment 8
With compound 17 α-pregnant steroid-6-alkene-3 β, 5 beta-diols-21, (2.0g 5.6mmol) is dissolved in the glycol dimethyl ether (520mL) 17-carboxylic lactone, stirs, and adds Zn-Cu preparation (7.5g), methylene iodide (6mL).Be warming up to 75 ℃~80 ℃, insulation reaction 4h.After reaction finishes, be cooled to room temperature, add methylene dichloride (500mL) dilution, use saturated aqueous ammonium chloride, water washing successively; Anhydrous magnesium sulfate drying, vacuum extraction is removed and is desolvated recrystallization, vacuum-drying; Obtain target compound 6 β, 7 β-methylene radical-17 α-pregnant steroid-3 β, 5 beta-diols-21,17-carboxylic lactone; White solid, 1.4g (3.7mmol, 66%).
Embodiment 9
With 4 β, 5 beta epoxides-Δ
6-Cetadiol, (2.0g 6.6mmol) adds in the glycol dimethyl ether (50mL) 17-isoallopregnane-3, stirs, and adds Zn-Cu preparation (13g), methylene iodide (6mL).Be warming up to 70 ℃~80 ℃, insulation reaction 4h.After reaction finishes, be cooled to room temperature, add methylene dichloride (50mL) dilution, use saturated aqueous ammonium chloride, water washing successively; Anhydrous magnesium sulfate drying, vacuum extraction is removed and is desolvated recrystallization, vacuum-drying; Obtain target compound 6 β, 7 β-methylene radical-androstane-3 β, 5 β, 17 beta-triols; White solid, and 1.2g (60%, 3.9mmol); Mp:206~208 ℃.
Embodiment 10
Under room temperature, to being dissolved with Δ
4,6-male diene-3, the 17-diketone ((332mg, 8.2mmol), spend the night to add Peng Qinghuana among the 1.0g, anhydrous THF solution 3.5mmol) (100mL) by insulated and stirred.The reaction final vacuum extracting that finishes removes solvent and gets white solid.This white solid is placed water, stir 30min.Use dichloromethane extraction (3 * 100mL) then.Organic layer is used sodium bicarbonate aqueous solution, water washing successively, and anhydrous magnesium sulfate drying filters, and concentrates, and ETHYLE ACETATE/normal hexane (1: 2) recrystallization obtains Δ after the vacuum-drying
4,6-male diene-3 β, 17-isoallopregnane-3, white crystals, 663mg (66%, 2.3mmol); Mp:154~157 ℃.
The above; It only is preferred embodiment of the present invention; Be not that the present invention is done any restriction, every technical spirit changes any simple modification, change and the equivalent structure that above embodiment did according to the present invention, all still belongs in the protection domain of technical scheme of the present invention.
Claims (9)
1. β, 7 β-methylene radical-steroidal-3 β, the preparation method of 5 beta-diols is characterized in that this method may further comprise the steps:
Step 1, be raw material, prepare compound 3 through reduction reaction with compound 2;
Step 2, the compound in the step 13 is made compound 4 through epoxidation reaction;
Step 3, the compound in the step 24 is made midbody 5 through reductive ring open reaction, midbody 5 makes target compound 1 through cyclopropanization reaction, perhaps directly makes target compound 1 through cyclopropanization reaction by compound 4;
2. according to described a kind of 6 β of claim 1; 7 β-methylene radical-steroidal-3 β; The preparation method of 5 beta-diols is characterized in that: the reductive agent that adopts in the reduction reaction described in the step 1 is the tetrahydrofuran solution of Peng Qinghuana, sodium cyanoborohydride, POTASSIUM BOROHYDRIDE 97MIN, lithium borohydride, zinc borohydride, three-methoxyl group Peng Qinghuana, three-ethyl lithium borohydride, three-sec.-butyl lithium borohydride, three-sec.-butyl POTASSIUM BOROHYDRIDE 97MIN, three-isopropoxy POTASSIUM BOROHYDRIDE 97MIN, aluminium lithium hydrogen, three-tertiary butyl aluminium lithium hydrogen, Di-Isobutyl aluminum hydride, diborane, borine, dimethyl sulphide solution, aluminium alkane, Raney Ni, samarium diodide, triethyl silicon hydrogen or the zinc powder of borine;
The reaction solvent that adopts in the said reduction reaction is methyl alcohol, ethanol, Virahol, acetone, chloroform, 1,4-dioxane, ETHYLE ACETATE, acetonitrile, ether, benzene, pyridine, THF, methylene dichloride, DMF or DMSO; Temperature of reaction in the reduction reaction is 0 ℃~70 ℃;
Said reductive agent consumption is 1~10 times of molar equivalent of compound 2.
3. according to described a kind of 6 β of claim 2,7 β-methylene radical-steroidal-3 β, the preparation method of 5 beta-diols is characterized in that: said temperature of reaction is 0 ℃~35 ℃; Said reductive agent consumption is 1~3 times of molar equivalent of compound 2.
4. according to described a kind of 6 β of claim 1; 7 β-methylene radical-steroidal-3 β; The preparation method of 5 beta-diols is characterized in that: the epoxidation reagent that adopts in the epoxidation reaction described in the step 2 is metachloroperbenzoic acid, Peracetic Acid, tertbutyl peroxide/VO (acac)
2System, potassium permanganate/nitrate salt system, trifluoroacetone/Oxone system or bisoxirane;
The reaction solvent that adopts in the said epoxidation reaction is toluene, benzene, acetone, acetonitrile, methylene dichloride or DMSO; Temperature of reaction in the said epoxidation reaction is 0 ℃~70 ℃;
Said epoxidation reagent consumption is 1~10 times of molar equivalent of compound 3.
5. according to described a kind of 6 β of claim 4,7 β-methylene radical-steroidal-3 β, the preparation method of 5 beta-diols is characterized in that: said epoxidation reagent is metachloroperbenzoic acid, Peracetic Acid or tertbutyl peroxide; Said reaction solvent is toluene or methylene dichloride; Said temperature of reaction is 0 ℃~35 ℃; Said epoxidation reagent consumption is 1~3 times of molar equivalent of compound 3.
6. according to described a kind of 6 β of claim 1; 7 β-methylene radical-steroidal-3 β; The preparation method of 5 beta-diols is characterized in that: the reductive ring open reagent that adopts in the reaction of reductive ring open described in the step 3 is the tetrahydrofuran solution of Peng Qinghuana, sodium cyanoborohydride, POTASSIUM BOROHYDRIDE 97MIN, lithium borohydride, zinc borohydride, three-methoxyl group Peng Qinghuana, three-ethyl lithium borohydride, three-sec.-butyl lithium borohydride, three-sec.-butyl POTASSIUM BOROHYDRIDE 97MIN, three-isopropoxy POTASSIUM BOROHYDRIDE 97MIN, lithium aluminum hydride, three-tertiary butyl aluminium lithium hydrogen, Di-Isobutyl aluminum hydride, diborane, borine, dimethyl sulphide solution, aluminium alkane, Raney Ni, samarium diodide, triethyl silicon hydrogen, zinc ethyl or the zinc powder of borine;
The reductive ring open reaction solvent that adopts in the said reductive ring open reaction is methyl alcohol, ethanol, Virahol, acetone, chloroform, 1,4-dioxane, ETHYLE ACETATE, acetonitrile, ether, benzene, pyridine, THF, methylene dichloride, THF, DMF or DMSO;
Temperature of reaction in the said reductive ring open reaction is-10 ℃~90 ℃;
Said reductive ring open reagent dosage is 1~10 times of molar equivalent of compound 4.
7. according to described a kind of 6 β of claim 6,7 β-methylene radical-steroidal-3 β, the preparation method of 5 beta-diols is characterized in that: said reductive ring open reagent is lithium aluminum hydride, zinc powder or Peng Qinghuana; Said reductive ring open reaction solvent is methylene dichloride or THF; Said temperature of reaction is 0 ℃~35 ℃; Said reductive ring open reagent dosage is 1~3 times of molar equivalent of compound 4.
8. according to described a kind of 6 β of claim 1; 7 β-methylene radical-steroidal-3 β; The preparation method of 5 beta-diols is characterized in that: the cyclopropanation reagents that cyclopropanization reaction described in the step 3 adopts is methylene iodide, methylene bromide or sulfur ylide, and employed initiator is an iodine; Employed catalyzer is Zn-Cu powder or zinc ethyl; Employed reaction solvent is methyl glycol, glycol dimethyl ether, 1,4-dioxane, DMSO or THF, and temperature of reaction is 0 ℃~90 ℃; Said cyclopropanation reagents consumption is 1~10 times of molar equivalent of compound 4.
9. according to described a kind of 6 β of claim 8; 7 β-methylene radical-steroidal-3 β; The preparation method of 5 beta-diols is characterized in that: said catalyzer is the Zn-Cu powder, and said reaction solvent is glycol dimethyl ether or DMSO; Said temperature of reaction is 10 ℃~80 ℃, and said cyclopropanation reagents consumption is 1~3 times of molar equivalent of compound 4.
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