CN106496297A - A kind of preparation method of stanolone - Google Patents
A kind of preparation method of stanolone Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
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Abstract
A kind of preparation method of stanolone, i.e., with 4 androstenedione（Abbreviation 4AD）For raw material, first by 4AD with triethyl orthoformate in organic solvent, acid catalyzed reaction obtains 33,5 diene of ethyoxyl androstane of etherate, 17 ketone；Again etherate is dissolved in organic solvent, metallic boron hydridess reducing agent is added, 17 ketone groups in etherate molecule is reduced into hydroxyl, 33,5 diene of ethyoxyl androstane of reduzate, 17 alcohol is obtained；Then reduzate is dissolved in organic solvent, adds hydrogenation catalyst, 5 double bonds in selective hydrogenation reduction thing molecule to obtain 3 ethyoxyl androstane of hydride, 3 alkene, 17 alcohol；Hydride by organic solvent, acid-catalyzed hydrolysis obtain stanolone finally；, compared with conventional production methods, raw material sources are wide, and synthetic route is short, simple process environmental protection for the inventive method, and product yield is high, economic and environment-friendly, and production cost reduces by 35 40%, is very beneficial to industrialized production.
Description
Technical field
The invention belongs to the fabricating technology field of steroid hormone medicine, and in particular to male to a kind of androgen drug
The preparation method of nandrolone.
Background technology
Stanolone, call dihydrotestosterone, be a kind of androgen drug, be clinically primarily to facilitate male genitals and
The development of secondary sexual characteristicss simultaneously maintains its normal function, is also used for the various diseases caused because male testical endocrine dysfunction is low,
Simultaneously can be used for synthesizing other senior androgen drugs such as dehydrogenation Testosterone, market application foreground is wide.The biography of stanolone
System production method, is extraction diosgenin from Rhizoma Dioscoreae plant, through protection, oxicracking, elimination, obtains key intermediate vinegar
Sour gestation diene alcohol ketone（Abbreviation diene）For raw material, through oximate, Beckmann rearrangement, reduction, basic hydrolysiss, oxidation, catalytic hydrogenation etc.
Six-step process is obtained, and its synthetic route is shown in accompanying drawing 1.Wherein the extraction of diosgenin, oxicracking, Beckmann rearrangement, reduction,
The techniques such as basic hydrolysiss, oxidation reaction, generation waste water are more, not disposable, easily pollute environment.Importantly, with wild potato
Chinese yam plant resourceses increasingly depleted, and artificial growth Rhizoma Dioscoreae plant, also because of the increasingly rising of the planting costs such as artificial, chemical fertilizer, cause
Saponin, the production cost of diene are doubled and redoubled, and cause stanolone production cost to increase substantially with the market price, already to global male
Nandrolone pharmaceutical market generates significant impact.
Content of the invention
It is an object of the invention to provide a kind of preparation method of new stanolone, solves synthesis material in traditional processing technology
The problems such as expensive, synthetic route length, complex operation, environmental protection treatment are difficult, production cost is high.To realize that Simplified flowsheet is operated, drop
Low production cost, reduces the purposes such as discharge of wastewater.
The technical scheme is that：A kind of preparation method of stanolone, with 4-AD（Abbreviation 4AD）For raw material,
Etherified, reduction, catalytic hydrogenation, hydrolysis four-step reaction synthesis stanolone；Operating procedure is as follows：
A, synthesis etherate, are that acid catalyzed reaction obtains etherate 3- by 4AD and triethyl orthoformate in low-carbon alcohols organic solvent
Ethyoxyl-androstane -3,5- diene -17- ketone；
B, synthesis reduzate, are to dissolve in etherate in organic solvent, add metallic boron hydridess reducing agent, by etherate molecule
In 17 ketone groups be reduced into hydroxyl, obtain reduzate 3- ethyoxyls-androstane -3,5- diene -17- alcohol；
C, synthesizing hydrogenated thing, are to dissolve in reduzate in organic solvent, add hydrogenation catalyst, selective hydrogenation reduction thing
5 double bonds in molecule, obtain hydride 3- ethyoxyls-androstane -3- alkene -17- alcohol；
D, synthesizing methyl Testosterone, be by hydride in organic solvent, acid-catalyzed hydrolysis obtain stanolone；
Further, the concrete operations which synthesizes are as follows：
A, the synthesis of etherate：By 4AD in organic solvent with triethyl orthoformate under acid catalysiss, anti-in 20～50 DEG C of stirrings
Answer 12～16 hours, after having reacted, add weak base to be neutralized to pH 7～7.5, further work-up, obtain etherate 3- ethyoxyls-
Androstane -3,5 diene -17- ketone, its HPLC content 98.5～99.5%, weight yield 100～102%；
B, the synthesis of reduzate：Above-mentioned etherate is dissolved in organic solvent, is stirred, temperature control is slowly added into gold to 10-50 DEG C
Category borohydride reduction agent, adds for 1 ~ 1.5 hour, then is incubated in 10-50 DEG C of continuation stirring reaction 3-4 hour, and TLC confirms anti-
Terminal is answered, after having reacted, adds acid to be neutralized to pH7 ~ 7.5, further work-up obtains reduzate 3- ethyoxyls-androstane -3,5 two
Alkene -17- alcohol, its HPLC content 98.0～99.0%, weight yield 90～95%；
C, the synthesis of hydride：Above-mentioned reduzate is dissolved in organic solvent, is stirred, temperature control adds hydrogenation to 10-50 DEG C
Catalysts, after displaced air, are slowly passed through hydrogen, are incubated and react 8～10 hours in 10～50 DEG C, and HPLC confirms reaction eventually
After point, hydrogen is drained, inflated with nitrogen filter pressing while hot, filter cake are reclaimed after being washed with appropriate solvent, and filtrate is merged with washing liquid, concentrating under reduced pressure
Organic solvent 90-95% is reclaimed, tap water stirring and crystallizing 2-3 hour is subsequently adding, is filtered, washing is dried, obtains hydride crude product,
HPLC contents 96.5-98.5%, weight yield 90～95%；Crude product obtains 3 ethoxy of hydride with ethanol, activated carbon decolorizing recrystallization
Base-androstane 3- alkene -17- alcohol, HPLC contents more than 99.0%, this step react weight yield 80～85%；
D, the synthesis of stanolone：Above-mentioned hydride is dissolved in organic solvent, is stirred, is incubated at 20～80 DEG C slowly Deca
Acid, reacts after adding 4～5 hours again, after TLC confirms reaction end, with liquid adjusting PH with base to 6.8 ~ 7.2, reclaims organic solvent, drop
Warm water is analysed, and obtains stanolone crude product, HPLC contents 98.0-99.0%, weight yield 80-85%；Crude product is tied again with below C4 low-carbon alcohols
Crystalline substance, obtains stanolone product, and 178～183 DEG C of fusing point, HPLC contents 99.0-99.5%, this step yield 75-78%, four-step reaction synthesize
Total recovery 60-65%.
Further, organic solvent described in above-mentioned etherate synthesis, including dichloromethane, toluene, below C4 low-carbon alcohols
Such as methanol, ethanol, preferably ethanol, safety and environmental protection, convenient recovery；Reaction acid catalyst used include mineral acid such as hydrochloric acid,
Sulphuric acid, phosphoric acid, or organic acid such as acetic acid, p-methyl benzenesulfonic acid, oxalic acid, preferably p-methyl benzenesulfonic acid, catalytic effect are good；Neutralization institute
Include sodium carbonate, or pyridine with weak base, 20～50 DEG C of reaction temperature, best 20～30 DEG C；The weight proportion of reactant is：4AD：
Triethyl orthoformate：Acid=1g：0.5～1.0g:0.01～0.05g；Preferably 1g：0.8g：0.02g；Between reactant and solvent
Proportioning be：4AD：Organic solvent=1g：2～8ml, is 1g::6～8ml.
The organic solvent of reduction reaction described in above-mentioned reduzate synthesis, including below C4 low-carbon alcohols such as methanol, ethanol,
DME, tetrahydrofuran, preferably ethanol, not only reaction effect is good, and safety and environmental protection；The reducing agent metal boron hydrogen of reduction reaction
Compound includes sodium borohydride, potassium borohydride, calcium borohydride, and best sodium borohydride is good and cheap；Reduction reaction temperature 10～50
DEG C, preferably 20～25 DEG C, the weight proportion between reactant is：Etherate：Reducing agent=1g：0.10～0.15g, preferably
1g：0.12g；Proportioning between reactant and solvent is：Etherate：Reaction organic solvent=1g：4～6ml, preferably 1g：5ml.
The organic solvent of hydrogenation described in above-mentioned hydride synthesis, including below C4 low-carbon alcohols such as methanol, ethanol,
DME, ethyl acetate, tetrahydrofuran, glacial acetic acid, preferably ethanol, not only reaction effect is good, and safety and environmental protection；Catalyst
Activity has very big impact, hydrogenation catalyst metal to include various containing the selectivity for reacting with consumption and reaction temperature
The palladium charcoal of amount, active nickel, preferably 5% palladium carbon, reaction effect are preferable；The reaction temperature of hydrogenation reaction is 10～50 DEG C, best
It it is 20～25 DEG C, the weight proportion between reactant is：Etherate：Catalyst：Hydrogen=1g：0.05～0.15g：0.05 ~ 0.10g,
Preferably 1g：0.08g:0.06g；Proportioning between reactant and solvent is：Etherate：Reaction organic solvent=1g：4～10ml, most
It is 1g well：8ml.
Organic solvent used by above-mentioned hydride hydrolysis stanolone, including toluene, acetone, below C4 unary fatty acids
Such as formic acid, acetic acid, below C4 low-carbon alcohols such as methanol, ethanol, isopropanol, tert-butyl alcohol etc., preferably acetic acid or ethanol, reaction effect
Good, convenient recovery；The acid includes mineral acid such as hydrochloric acid, sulphuric acid, or organic acid such as trifluoroacetic acid, p-methyl benzenesulfonic acid, preferably
Hydrochloric acid, inexpensive environmental protection；40～80 DEG C of reaction temperature, best 60～65 DEG C；Weight proportion between reactant is：Hydride：Acid=
1g：0.6～1.2g, preferably 1g：0.8g；Proportioning between reactant and solvent is, hydride：Organic solvent=1g：4-6ml, most
It is 1g well：5ml.
The invention has the beneficial effects as follows：Due to using the residual stigmasterol for looking into middle extraction after processing from soybean oil fermented after
4AD is obtained for raw material, compared with the method for raw material is made with diosgenin, extensively, production cost reduces raw material sources；Present invention side
, compared with conventional production methods, synthetic route is short for method, simple process environmental protection, and product yield is high, and quality is good, with current raw material valency
Lattice are calculated, and raw materials for production cost reduces 35-40%；The recyclable recycled of solvent used in technique, both economical, and environmental protection, ten
Divide and be beneficial to industrialized production.
Description of the drawings
Fig. 1 is stanolone traditional processing technology route map；
Fig. 2 is stanolone synthetic route chart of the present invention.
Specific embodiment
In order to illustrate in greater detail the main points of the present invention and spirit, name three embodiments and be explained：
Embodiment one
A, the preparation of etherate
In a 1000ml there-necked flask, addition 100g 4AD, 200ml ethanol, 80ml triethyl orthoformates, 2g is to toluene sulphur
Acid, is incubated in 20～25 DEG C of stirring reactions 12～16 hours, and TLC detects reaction end, and after react, addition 3ml pyridines are stirred
Mixing 20-25 minutes neutralizes acid, and system is cooled to -5-0 DEG C then, stirred crystallization 2～3 hours, sucking filtration, a small amount of washing with alcohol,
Washing liquid and filtrate merge, and recycling design and crude product are applied mechanically；Dry below 70 DEG C of filter cake, obtain etherate 101.6g, HPLC contents
99.2%, weight yield 101.6%.
B, the preparation of reduzate
In a 1000ml there-necked flask, 100g etherates, 800ml ethanol, stirring is added to be warming up to 20～25 DEG C, be slowly added into
12g sodium borohydrides, about 0.5-1.0 hours are added, and are further continued for insulated and stirred and are reacted 2～3 hours, after TLC detection reaction ends, slowly
To pH6.5-7.0, after dripping off, concentrating under reduced pressure reclaims the solvent of 90-95% to slow Deca 0.1N hydrochloric acid, is subsequently adding 500ml originally
Water, stirring and crystallizing 2-3 hour are filtered, and washing is dried, obtains reduzate crude product 92.6g, HPLC contents 98.5%, weight yield
92.6%.600ml ethanol, heating will be added again in above-mentioned crude product to dissolve which, add 5g activated carbons, reflux decolour 1～1.5 is little
When, filtered while hot, filter cake about 80ml ethanol foam washings, merging filtrate and washing liquid, normal pressure are concentrated into about 85% ethanol of recovery, then will
System is cooled to 0～5 DEG C, stirring and crystallizing 2～3 hours, filters, and filter cake is washed with the ethanol solution of 10ml 50%, less than 70 DEG C
Dry, obtain reduzate 84.6g, HPLC contents 99.2%, weight yield 84.6%.
C, the preparation of hydride
In a 1000ml there-necked flask, 100g reduzates, 800ml ethanol, stirring is added to be warming up to 20～25 DEG C, be slowly added into
The palladium charcoal of 8g 5%, after displaced air, starts slowly to be passed through hydrogen, and about 1-1.5 hours are until saturation, is further continued for insulated and stirred anti-
Answer 2～3 hours, TLC detects reaction end, drains hydrogen, nitrogen filter pressing, filter cake 80-100ml washing with alcohol after having reacted
Hou Song producers Recover palladium charcoal, filtrate and washing liquid merge, and concentrating under reduced pressure reclaims the solvent of 90-95%, is subsequently adding 500ml tap waters,
Stirring and crystallizing 2-3 hour, filters, and washing is dried, obtains hydride crude product 92.6g, HPLC contents 97.5%, weight yield 92.6%；
Again by above-mentioned crude product 600ml ethanol recrystallization, hydride 84.5g, HPLC contents 99.2%, weight yield 84.5% is obtained.
D, the preparation of stanolone
In a 1000ml there-necked flask, 100g hydrides, 500ml toluene, stirring is added to be slowly ramped to 60～65 DEG C, drip
The sulfuric acid solution 240ml for plus 50%, drips off for 1.5～2 hours, and after dripping off, insulation reaction 4～5 hours is cooled to 20- after having reacted
25 DEG C, point water, 2x200ml originally water washing, then vacuum distillations reclaim the toluene of about 90-95%, are subsequently adding 600 ml certainly
Water, is cooled to 10～15 DEG C, stirring and crystallizing 2-3 hour, filters, is washed to neutrality, dries, obtain stanolone below 70 DEG C of filter cake
Crude product 86.5g；HPLC contents 98.0%, yield 86.5%.By above-mentioned crude product 500ml ethanol recrystallization, stanolone 76.6g is obtained,
178～182 DEG C of fusing point, HPLC contents 99.4%, weight yield 76.6%.
Embodiment two
A, the preparation of etherate
In a 1000ml there-necked flask, addition 100g 4AD, 600ml dichloromethane, 80ml triethyl orthoformates, 2g is to toluene
Sulfonic acid, is incubated after 20～25 DEG C of stirring reactions 12～16 hours, TLC detection reaction ends, adds 3ml pyridines, and stirring 20～
Dichloromethane is reclaimed in neutralization acid in 25 minutes, concentrating under reduced pressure, and cooling adds 100ml ethanol, system is cooled to -5～0 then
DEG C, stirred crystallization 2～3 hours, sucking filtration, a small amount of washing with alcohol, washing liquid and filtrate merge, and recycling design and crude product are applied mechanically；Filter cake
Less than 70 DEG C dry, and obtain etherate 100.2g, HPLC contents 99.4%, weight yield 100.2%.
B, the preparation of reduzate
In a 1000ml there-necked flask, 100g etherates, 800ml methanol, stirring is added to be warming up to 20～25 DEG C, be slowly added into
12g potassium borohydrides, 0.5-1.0 hours are added, and are further continued for insulated and stirred and are reacted 2～3 hours, and TLC detects reaction end, has reacted
Afterwards, slowly Deca 0.1N hydrochloric acid, to pH6.5-7.0, drips off the solvent that rear concentrating under reduced pressure reclaims 90-95%, is subsequently adding 500ml certainly
Water, stirring and crystallizing 2-3 hour are filtered, and washing is dried, and obtain reduzate crude product 92.2g, and HPLC contains 98.0%, weight yield
92.2%；600ml ethanol, heating will be added again in above-mentioned crude product to dissolve which, add 5g activated carbons, reflux decolour 1～1.5 is little
When, filtered while hot, filter cake about 80ml ethanol foam washings, merging filtrate and washing liquid, normal pressure are concentrated into about 85% ethanol of recovery, then will
System is cooled to 0～5 DEG C, stirring and crystallizing 2～3 hours, filters, and filter cake is washed with the ethanol solution of 10ml 50%, less than 70 DEG C
Dry, obtain reduzate 84.0g, HPLC contents 99.4%, weight yield 84.0%.
C, the preparation of hydride
In a 1000ml there-necked flask, 100g reduzates, 800ml ethyl acetate, stirring is added to be warming up to 30～35 DEG C, slowly
The palladium charcoal of 8g 3% is added, after displaced air, starts slowly to be passed through hydrogen, 1-1.5 hours are until saturation, is further continued for insulated and stirred
Reaction 4～5 hours, TLC detect reaction end, after having reacted, drain hydrogen, nitrogen filter pressing, filter cake 80-100ml acetic acid second
Ester washing Hou Song producers Recover palladium charcoal, filtrate and washing liquid merge, and concentrating under reduced pressure reclaims the solvent of 90-95%, is subsequently adding 500ml
Tap water, stirring and crystallizing 2-3 hour are filtered, and washing is dried, and obtain hydride crude product 93.8g, and HPLC contents 97.8%, weight are received
Rate 93.8%；Again by above-mentioned crude product 600ml ethanol recrystallization, hydride 84.8g, HPLC contents 99.5%, weight yield is obtained
84.8%.
D, the preparation of stanolone
In a 1000ml there-necked flask, 100g hydrides, 500ml ethanol, stirring is added to be slowly ramped to 60～65 DEG C, drip
Plus the hydrochloric acid solution of 300ml 36%%, after 1.5～2 hours drip off, insulation reaction 4～5 hours is cooled to 20-25 after having reacted
Degree, adds 30% soda bath, is neutralized to pH value of solution 7.0-7.5, then vacuum distillation, reclaims the ethanol of about 90-95%, then
600ml tap waters are added, 10～15 DEG C are cooled to, stirring and crystallizing 2-3 hour filters, is washed to neutrality, dries below 70 DEG C of filter cake
Dry, obtain stanolone crude product 88.5g, HPLC contents 98.5%, yield 88.5%.By above-mentioned crude product 500ml ethanol recrystallization, obtain male
Nandrolone 78.0g, 178.5～182.5 DEG C of fusing point, HPLC contents 99.5%, weight yield 78.0%.
Embodiment three
A, the preparation of etherate
In a 1000ml there-necked flask, 100g 4AD, 200ml ethanol, 80ml triethyl orthoformates is added, HCl gases are passed through
2g, closed, it is incubated in 20-25 DEG C of stirring reaction 12～16 hours, TLC detects reaction end, after react, addition 3ml pyrroles
Pyridine, stirs neutralization acid in 20～25 minutes, system is cooled to -5～0 DEG C then, stirred crystallization 2～3 hours, sucking filtration, Shao Liangyi
Alcohol is washed, and washing liquid and filtrate merge, and recycling design and crude product are applied mechanically；Dry below 70 DEG C of filter cake, obtain etherate 103.2g, HPLC
Content 99.1%, weight yield 103.2%.
B, the preparation of reduzate
In a 1000ml there-necked flask, 100g etherates, 800ml methanol, stirring is added to be warming up to 20～25 DEG C, be slowly added into
12g sodium borohydrides, 0.5-1.0 hours are added, and are further continued for insulated and stirred and are reacted 2～3 hours, after TLC detection reaction ends, slowly
Deca 0.1N hydrochloric acid drips off the solvent that rear concentrating under reduced pressure reclaims 90-95%, is subsequently adding 500ml tap waters, stirs to PH6.5-7.0
Crystallize 2-3 hours are mixed, is filtered, washing is dried, obtains reduzate crude product 93.8g, HPLC contents 97.5%, weight yield 93.8%；Again
600ml ethanol will be added in above-mentioned crude product, heating makes its dissolving, addition 5g activated carbons, reflux decolour 1～1.5 hour, while hot mistake
Filter, filter cake about 80ml ethanol foam washings, merging filtrate and washing liquid, normal pressure are concentrated into about 85% ethanol of recovery, then system is cooled to
0～5 DEG C, stirring and crystallizing 2～3 hours is filtered, and filter cake is washed with the ethanol solution of 10ml 50%, and less than 70 DEG C dry, and must reduce
Thing 84.8g, HPLC content 99.5%, weight yield 84.8%.
C, the preparation of hydride
In a 1000ml there-necked flask, 100g reduzates, 800ml ethanol, stirring is added to be warming up to 30～35 DEG C, be slowly added into
3% active nickels of 10g, after displaced air, start slowly to be passed through hydrogen, and about 1-1.5 hours are until saturation, is further continued for insulated and stirred
Reaction 4～5 hours, TLC detect reaction end, after having reacted, drain hydrogen, and nitrogen filter pressing, filter cake are washed with 80-100ml ethanol
Di Housong producers reclaim metallic nickel, and filtrate and washing liquid merge, and concentrating under reduced pressure reclaims the solvent of 90-95%, are subsequently adding 500ml certainly
Water, stirring and crystallizing 2-3 hour are filtered, and washing is dried, obtains hydride crude product 91.5g, HPLC contents 97.6%, weight yield
91.5%；Again by above-mentioned crude product 600ml ethanol recrystallization, hydride 82.6g, HPLC contents 99.3%, weight yield is obtained
82.6%.
D, the preparation of stanolone
In a 1000ml there-necked flask, 100g hydrides, 500ml toluene, stirring is added to be slowly ramped to 60～65 DEG C, drip
Plus the hydrobromic acid solution of 240ml 42%%, drip off within 1.5～2 hours, drip off rear insulation reaction 4～5 hours, cooling after having reacted
To 20-25 degree, 30% soda bath is added, pH value of solution 7.0-7.5 is neutralized to, point water layer, then vacuum distillation to the greatest extent is reclaimed about
The toluene of 90-95%, is subsequently adding 600 ml tap waters, is cooled to 10～15 DEG C, stirring and crystallizing 2-3 hour, filters, is washed to
Neutrality, dries below 70 DEG C of filter cake, obtains stanolone crude product 87.5g, HPLC contents 97.8%, yield 87.5%.Above-mentioned crude product is used
500ml ethanol recrystallization, obtain stanolone 75.2g, 179.5～182.5 DEG C of fusing point, HPLC contents 99.6%, weight yield 75.2%.
Claims (4)
1. a kind of preparation method of stanolone, with 4-AD（Abbreviation 4AD）For raw material, etherified, reduction, catalytic hydrogenation,
Hydrolysis four-step reaction synthesis stanolone；Operating procedure is as follows：
A, synthesis etherate, by 4AD and triethyl orthoformate in low-carbon alcohols organic solvent, acid catalyzed reaction obtains etherate 3- second
Epoxide-androstane -3,5- diene -17- ketone；
B, synthesis reduzate, etherate is dissolved in organic solvent, metallic boron hydridess reducing agent is added, by etherate molecule
17 ketone groups be reduced into hydroxyl, obtain reduzate 3- ethyoxyls-androstane -3,5- diene -17- alcohol；
C, synthesizing hydrogenated thing, reduzate is dissolved in organic solvent, adds hydrogenation catalyst, selective hydrogenation reduction thing point
5 double bonds in son, obtain hydride 3- ethyoxyls-androstane -3- alkene -17- alcohol；
D, synthesis stanolone, acid-catalyzed hydrolysis obtain stanolone by hydride in organic solvent.
2. the preparation method of stanolone according to claim 1, is characterized in that, concrete operations are as follows：
A, the synthesis of etherate：By 4AD in organic solvent with triethyl orthoformate under acid catalysiss, anti-in 20～50 DEG C of stirrings
Answer 12～16 hours, after having reacted, add weak base to be neutralized to pH 7～7.5, further work-up, obtain etherate 3- ethyoxyls-
Androstane -3,5 diene -17- ketone, its HPLC content 98.5～99.5%, weight yield 100～102%；
B, the synthesis of reduzate：Above-mentioned etherate is dissolved in organic solvent, is stirred, temperature control is slowly added into gold to 10-50 DEG C
Category borohydride reduction agent, adds for 1 ~ 1.5 hour, then is incubated in 10-50 DEG C of continuation stirring reaction 3-4 hour, and TLC confirms anti-
Terminal is answered, after having reacted, adds acid to be neutralized to pH7 ~ 7.5, further work-up obtains reduzate 3- ethyoxyls-androstane -3,5 two
Alkene -17- alcohol, its HPLC content 98.0～99.0%, weight yield 90～95%；
C, the synthesis of hydride：Above-mentioned reduzate is dissolved in organic solvent, is stirred, temperature control adds hydrogenation anti-to 10-50 DEG C
Catalyst is answered, after displaced air, slowly hydrogen is passed through, is incubated and is reacted 8～10 hours in 10～50 DEG C, HPLC confirms reaction end
Afterwards, hydrogen is drained, while hot inflated with nitrogen filter pressing, filter cake is reclaimed after being washed with appropriate solvent, and filtrate is merged with washing liquid, and concentrating under reduced pressure is returned
Organic solvent 90-95% is received, tap water stirring and crystallizing 2-3 hour is subsequently adding, is filtered, washing is dried, obtains hydride crude product,
HPLC contents 96.5-98.5%, weight yield 90～95%；Crude product obtains 3 ethoxy of hydride with ethanol, activated carbon decolorizing recrystallization
Base-androstane 3- alkene -17- alcohol, HPLC contents more than 99.0%, this step react weight yield 80～85%；
D, the synthesis of stanolone：Above-mentioned hydride is dissolved in organic solvent, is stirred, is incubated at 20～80 DEG C slowly Deca
Acid, reacts after adding 4～5 hours again, after TLC confirms reaction end, with liquid adjusting PH with base to 6.8 ~ 7.2, reclaims organic solvent, drop
Warm water is analysed, and obtains stanolone crude product, HPLC contents 98.0-99.0%, weight yield 80-85%；Crude product is tied again with below C4 low-carbon alcohols
Crystalline substance, obtains stanolone product, and 178～183 DEG C of fusing point, HPLC contents 99.0-99.5%, this step yield 75-78%, four-step reaction synthesize
Total recovery 60-65%.
3. the preparation method of stanolone according to claim 1 or claim 2, is characterized in that,
In A, etherate synthesis, the organic solvent includes dichloromethane, toluene, methanol, ethanol, reaction acid catalyst used
Including hydrochloric acid, sulphuric acid, phosphoric acid, or acetic acid, p-methyl benzenesulfonic acid, oxalic acid；Weak base used by neutralization includes sodium carbonate or pyridine, reaction temperature
20～50 DEG C of degree；The weight proportion of reactant is, 4AD：Triethyl orthoformate：Acid=1g：0.5～1.0g:0.01～0.05g；
Proportioning between reactant and solvent is, 4AD：Organic solvent=1g：2～8ml；
In B, reduzate synthesis, described organic solvent includes methanol, ethanol, DME, tetrahydrofuran, reducing agent metal hydroboration
Thing includes sodium borohydride, potassium borohydride, calcium borohydride；10～50 DEG C of reaction temperature；Weight proportion between reactant is to be etherified
Thing：Reducing agent=1g：0.10～0.15g, the proportioning between reactant and solvent is, etherate：Organic solvent=1g：4～6ml；
In C, hydride synthesis, described organic solvent includes below C4 low-carbon alcohols such as methanol, ethanol, DME, ethyl acetate, four
Hydrogen furan, glacial acetic acid, hydrogenation catalyst metal include palladium charcoal, active nickel；10～50 DEG C of the reaction temperature of hydrogenation reaction；Instead
The weight proportion between thing is answered to be, etherate：Catalyst：Hydrogen=1g：0.05～0.15g：0.05 ~ 0.10g, reactant and solvent
Between proportioning be, etherate：Reaction organic solvent=1g：4～10ml；
D, hydride hydrolysis used by organic solvent, including toluene, acetone, formic acid, acetic acid, below C4 low-carbon alcohols for example methanol, ethanol,
Isopropanol, the tert-butyl alcohol, the acid include hydrochloric acid, sulphuric acid, or trifluoroacetic acid, p-methyl benzenesulfonic acid, 40～80 DEG C of reaction temperature；Reaction
Weight proportion between thing is, hydride：Acid=1g：0.6～1.2g, the proportioning between reactant and solvent is, hydride：Organic molten
Agent=1g：4-6ml.
4. the preparation method of stanolone according to claim 1 or claim 2, is characterized in that,
A, the organic solvent of etherate synthesis are ethanol, and acid catalyst used is p-methyl benzenesulfonic acid；Neutralization reaction temperature 20～
30 DEG C, the weight proportion of reactant is, 4AD：Triethyl orthoformate：Acid=1g：0.8g：0.02g；Matching somebody with somebody between reactant and solvent
Than 4AD：Organic solvent=1g::6～8ml；
B, the organic solvent of reduction reaction are ethanol, and reducing agent is sodium borohydride, 20～25 DEG C of reaction temperature, the weight between reactant
Measuring proportioning is, etherate：Reducing agent=1g：0.12g；Etherate：Organic solvent=it is 1g：5ml；
C, the organic solvent of hydrogenation are ethanol, and catalyst is 5% palladium carbon；20～25 DEG C of the reaction temperature of hydrogenation reaction, instead
The weight proportion between thing is answered to be, etherate：Catalyst：Hydrogen=1g：0.08g:0.06g；Etherate：Organic solvent=1g：8ml；
D, organic solvent used by hydride hydrolysis are acetic acid or ethanol, and it is hydrochloric acid to hydrolyze the acid, 60～65 DEG C of reaction temperature；Instead
The weight proportion between thing is answered to be, hydride：Acid=1g：0.8g；Hydride：Organic solvent=1g：5ml.
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