CN107312051A - The preparation method of Mestanlone - Google Patents
The preparation method of Mestanlone Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- 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
- C07J1/0003—Androstane derivatives
- C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
- C07J1/0037—Androstane derivatives substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being a saturated hydrocarbon group
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Abstract
The preparation method of Mestanlone, using 4AD as raw material, by its with triethyl orthoformate in the organic solvents such as low-carbon alcohols, acid catalyzed reaction obtains etherate；With methyl-magnesium-halide RMgBr grignard addition reaction is occurred into for the etherate in organic solvent, the alcohol of 33,5 diene of ethyoxyl 17a methyl androstanes of grignard thing 17 is obtained；Then it is catalyzed with palladium charcoal, 5 double-bond hydrogenations of grignard thing are obtained into the ketone of 3 ethyoxyl androstane of hydride, 3 alkene 17, finally by the hydride in the organic solvents such as low-carbon alcohols, Mestanlone crude product is obtained with acid-catalyzed hydrolysis, then Mestanlone is refining to obtain with alcohol, decolorizing with activated carbon.HPLC contents more than 99.5%, 192.5 194.0 DEG C of fusing point, synthesis weight total recovery 76 83%.Raw material of the present invention is cheap and easy to get, and technological operation is easy, good product purity, high income, and solvent recovering rate is high, production cost reduction by 25 30%；Beneficial to industrialized production.
Description
Technical field
The invention belongs to the fabricating technology of steroid hormone pharmaceutical intermediate, and in particular to a kind of preparation of Mestanlone
Method.
Background technology
Mestanlone is a kind of important intermediate for producing steroid hormone medicine.Using it as raw material, can produce adroyd,
A variety of common androgen medicines such as stanozolol.
The conventional production methods of Mestanlone, are the Chinese yam saponins to be extracted in Chinese yam plant, through protection, oxicracking,
Eliminate, the pregnant diene alcohol ketone of acetic acid of acquisition（Abbreviation diene）For raw material, through oximate, rearrangement, grignard, hydrogenation, basic hydrolysis, oxygen
The six-step processes such as change are made, and its process route is shown in accompanying drawing 1.The wherein extraction of Chinese yam saponin, oxicracking, the oximate of diene, again
The techniques such as row, the oxidation of final step chromic anhydride, waste water is more and not disposable, easily pollutes environment.Importantly, with wild
Chinese yam plant resources increasingly depleted, and artificial growth Chinese yam plant, also because of the increasingly rising of the planting costs such as artificial, chemical fertilizer, lead
Saponin, the production cost of diene is caused to be doubled and redoubled, the production cost and the market price for causing Mestanlone increase substantially, to health
The world market of multiple dragon class androgen medicine generates significant impact.
The content of the invention
It is an object of the invention to provide a kind of new Mestanlone preparation method, solve raw material in existing production technology it is expensive,
Many defects such as sewage disposal hardly possible, complex operation, substantially reduce the production cost of Mestanlone.
The technical scheme is that：The preparation method of Mestanlone, with 4- androstene -3,17- diketone（Abbreviation 4AD）For original
Material, is etherified, 17 ketone grignards, 5 catalytic hydrogenations by 3 alkene of 4AD, and last acid-catalyzed hydrolysis four-step reaction synthesis is U.S. male
Nandrolone；It is raw material i.e. with 4AD, triethyl orthoformate makees reagent, acid catalysis prepares etherate 3- ethyoxyls-hero in organic solvent
Steroid -3,5- diene -17- ketone；In organic solvent, simultaneously sour water solves grignard to the etherate with the addition of methyl-magnesium-halide RMgBr
Thing 3- ethyoxyl -17a- methyl-androst -3,5- diene -17b- alcohol, the grignard thing uses palladium carbon catalytic hydrogenation in organic solvent,
Obtain hydride 3- ethyoxyl -17a- methyl-androst -17- alcohol；By this hydride, acid-catalyzed hydrolysis obtains U.S. male promise in organic solvent
Dragon.
The preparation method of Mestanlone, concrete operation step is as follows：
A, etherate preparation
4AD is dissolved in organic solvent, with triethyl orthoformate under acid catalysis, in 20-50 DEG C of stirring reaction 12-16 hours,
After having reacted, add weak base and be neutralized to pH7-7.5, etherate 3- ethyoxyls-androstane -3,5 diene -17- ketone is obtained after processing, its
HPLC content 98.5-99.5%, weight yield 100-102%；
B, grignard thing preparation
Organic solvent tetrahydrofuran or ether, metal magnesium chips are added in reaction bulb, 30-80 DEG C is warming up to, is then slowly added dropwise
Or methyl halogenated alkane is poured, until metal magnesium chips reacts disappearance completely, RMgBr is made, 10 DEG C or so of cooling is standby；Another
In one reaction bulb, above-mentioned etherate is dissolved in organic solvent, this etherate solution then is added dropwise into foregoing grignard tries
Grignard addition reaction is brought it about in agent, after dripping, continues insulation reaction 2-3 hours, until TLC shows that raw material has reacted
Entirely；Then, aqueous acid is slowly added dropwise and is incubated hydrolysis again 3-4 hours, TLC determines reaction end, then is slowly added into alkali lye
Be neutralized to pH6-7, then the recovery organic solvent that is concentrated under reduced pressure, finally add water crystallization, filtration drying, obtain grignard thing 3- ethyoxyls-
17a- methyl-androst -3,5- diene -17b- alcohol, its HPLC content 97.5%-98.5%, weight yield about 100-105%；
C, hydride preparation
Above-mentioned grignard thing is dissolved in organic solvent, 5% palladium carbon is added, with hydrogen is passed through after nitrogen displacement air, is warming up to
30-60 DEG C is reacted 8-10 hours, after having reacted, emptying, and nitrogen press filtration is used while hot, and a small amount of solvent washing, filter cake send producer to reclaim,
Washing lotion and filtrate merge, and reclaim elutriation after organic solvent, obtain solid；This solid wet product is directly tied again with alcohol, activated carbon decolorizing
Crystalline substance, obtains the ethyoxyl -17a- methyl-androst -3- alkene -17- alcohol of hydride 3, HPLC contents more than 99.0%, weight yield 85-90%；
D, Mestanlone preparation
Above-mentioned hydrogenation thing is dissolved in organic solvent, acid catalyst is added, 30-100 DEG C is warming up to, reacts 6-8 hours, has reacted
Afterwards, add alkali lye and be neutralized to pH6-7, then reclaim organic solvent, cool elutriation, obtains Mestanlone crude product；By above-mentioned crude product with
Alcohol, activated carbon decolorizing recrystallization, obtain Mestanlone, 192.5-194.0 DEG C of fusing point, content ＞ 99%, yield 80-85%.
The preparation method of Mestanlone, it is characterized in that,
A walks the organic solvent from one kind in dichloromethane, toluene, methanol, ethanol or two kinds；Reaction acid catalysis used
One kind that agent is selected in hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, p-methyl benzenesulfonic acid, oxalic acid；Neutralize weak base sodium carbonate used or pyrrole
Pyridine；Reaction temperature is 20-50 DEG C；Weight proportion between reactant is, 4AD：Triethyl orthoformate：Acid=1：0.5-1.0 :
0.01-0.05；Proportioning between reactant and solvent is, 4AD：Organic solvent=1：2-8；
B walks the organic solvent, from one kind in tetrahydrofuran derivatives cyclic ethers, chloroform, toluene, methyl ether, ether；Grignard is anti-
The one kind for answering methyl halogenated alkane used to select in bromomethane, chloromethanes, iodomethane；Acid catalyst used in hydrolysis selects salt
One kind in acid, sulfuric acid, phosphoric acid, p-methyl benzenesulfonic acid, oxalic acid；Neutralize alkali lye caustic soda used or sodium carbonate or ethamine；Grignard is anti-
It should be 30-80 DEG C with the reaction temperature of hydrolysis；Quality proportioning between reactant is, etherate：Magnesium：Alkyl halide：Acid=1：
0.08-0.25: 0.2-0.5：0.2-0.5；Proportioning between reactant and solvent is, etherate：RMgBr prepares organic molten
Agent：Grignard reaction organic solvent=1g：2-8ml： 5-15ml；
C walks the organic solvent, from one kind in ethanol, acetic acid, ethyl acetate, tetrahydrofuran, acetic acid, acetone；Catalyst
Be 5% palladium carbon, 30-60 DEG C of reaction temperature；Weight proportion between reactant is, grignard thing：Palladium carbon：Hydrogen=1：0.05-0.25：
0.01-0.15；Proportioning between reactant and solvent is, grignard thing：Organic solvent=1g：5-20ml；
D walks the organic solvent, from acetic acid, alcohol, toluene, chloroform, formic acid, acetic acid, ethanol, isopropanol, the tert-butyl alcohol
It is a kind of；The acid is from one kind in hydrochloric acid, hydrobromic acid, perchloric acid, sulfuric acid or acetic acid, p-methyl benzenesulfonic acid, and reaction temperature is
30-100℃；Weight proportion between reactant is to be hydrogenated with thing：Acid=1：0.15-0.25；Proportioning between reactant and solvent is, plus
Hydrogen thing：Organic solvent=1g：4-10ml.
Further, preferred parameter is as follows in the preparation method of Mestanlone：
A, etherate preparation, reaction acid catalyst used is p-methyl benzenesulfonic acid, neutralizes weak base used
It is pyridine, reaction temperature is that the weight proportion between 20-30 DEG C, reactant is, 4AD：Triethyl orthoformate：Acid=1: 0.8
:0.02；
B, grignard thing preparation, the organic solvent are tetrahydrofurans, and methyl halogenated alkane used in grignard reaction is bromomethane, hydrolysis
Reaction acid catalyst used is hydrochloric acid, and neutralization is soda bath, and the temperature of grignard reaction and hydrolysis is 40-60
DEG C, the quality (g) between reactant, which is matched, is, etherate：Magnesium：Alkyl halide：Acid=1: 0.20: 0.35 :0.35；Reactant with it is molten
Proportioning between agent is, etherate：RMgBr prepares organic solvent：Grignard reaction organic solvent is 1g ﹕ 5ml ﹕ 8ml;
C, hydride preparation, described organic solvent are ethanol or acetic acid, and catalyst is 5% palladium carbon, reaction temperature 40-45
℃；Quality (g) between reactant is matched, grignard thing：Palladium carbon：Hydrogen=1: 0.15 :0.10；Matching somebody with somebody between reactant and solvent
Than being, grignard thing：Organic solvent is 1g：10ml；
D, Mestanlone preparation, described organic solvent are acetic acid or alcohol, and the acid is hydrochloric acid,
Weight (g) proportioning between 50-60 DEG C of reaction temperature, reactant is to be hydrogenated with thing：Acid=1:0.2, between reactant and solvent
Proportioning is to be hydrogenated with thing：Organic solvent is 1g：6ml.
The beneficial effects of the invention are as follows：Mestanlone, the relative tradition for making raw material with Chinese yam saponin are produced using the present invention
Method, raw material 4AD wide material sources, synthetic route is economic and environment-friendly, and process conditions are gentle, and production operation is easy, and product yield is high, matter
Measure, production cost reduction 25-30%.The solvent used in technique, recyclable recycled was both economical and environmentally friendly, very sharp
In industrialized production.
Brief description of the drawings
Fig. 1 is existing Mestanlone production process route figure；
Fig. 2 is Mestanlone production process route figure of the present invention.
Embodiment
In order to more easily illustrate the main points and spirit of the present invention, citing below is explained：
Embodiment one
A, etherate preparation
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 reaction 12~16 hours, TLC detection reaction ends after react, add 3ml pyridines, stirred
Neutralize acid within 20-25 minutes, system is then cooled to -5-0 DEG C, stirred crystallization 2~3 hours, suction filtration, a small amount of ethanol washing is washed
Liquid and filtrate merge, and recycling design and crude product are applied mechanically；Dried below 70 DEG C of filter cake, obtain etherate 101.6g, HPLC content
99.2%, weight yield 101.6%.
B, grignard thing preparation
In a 2000ml there-necked flask, 20g metal magnesium chips is added, 500mlTHF is warming up to 40-45 DEG C, lead to nitrogen displacement
Afterwards, bromomethane, stirring reaction 8~10 hours are slowly passed through, until metal reactive magnesium is complete.After having reacted, stopping is passed through bromine first
RMgBr is obtained after alkane, logical nitrogen displacement, it is standby.The above-mentioned etherates of 100g are added in another 1000ml reaction bulb, plus
Enter 800mlTHF, being stirred at room temperature makes its dissolving complete, and then this etherate solution is added in a 1000ml dropping funel,
And this dropping funel is placed on above-mentioned 2000ml there-necked flasks, in 40-45 DEG C, then slowly above-mentioned standby RMgBr is incubated
Slowly the THF solution of above-mentioned etherate is added dropwise, drips off within about 1-1.5 hours, and continues insulation reaction 3-4 hours, TLC detections, until
Grignard reaction completely, after having reacted, is slowly added dropwise to 350ml 10% hydrochloric acid, in 40-45 DEG C of insulated and stirred, acidolysis reaction 3-4
Hour, TLC detections, after acidolysis reaction is complete, the soda bath of addition 10% is neutralized to the PH 6.5 of system, then subtracts system
Concentration and recovery about 90-95% solvent THF is pressed, slightly cools down, adds 500ml running water, 5-10 DEG C is cooled to, stirred crystallization 2~
3 hours, suction filtration was washed, and is dried below 70 DEG C of filter cake, is obtained grignard thing 102.8g, HPLC content 99.2%, weight yield 102.8%.
C, the preparation for being hydrogenated with thing
In a 2000ml there-necked flask, 100g grignard thing, 1000ml ethanol are added, 15g 5% palladium carbon is added after dissolving, is risen
Temperature is to 40-45 DEG C, after nitrogen displacement, is passed through hydrogen, and insulated and stirred is reacted 8~10 hours, TLC detection reaction ends, reaction
After complete, nitrogen displacement, nitrogen press filtration while hot, 50ml ethanol washing, filter cake send producer to reclaim；Washing lotion and filtrate merge, and depressurize dense
Contracting, reclaims ethanol and applies mechanically.Residual night adds 600ml running water elutriations, filtering, obtains solid hydrogenation thing crude product.Above-mentioned solid is hydrogenated with thing
Crude product is directly added in 800ml alcohol, and heating dissolves it, adds 5g activated carbons, and flow back decolouring 1-1.5 hours, while hot mistake
Filter, filter cake about 80ml alcohol foam washings, merging filtrate and washing lotion, normal pressure are concentrated into about 85% alcohol of recovery, then add 50ml pure
Water purification, continues to steam about 100ml 50-60% containing ethanol solvent, then system is cooled into 5-10 DEG C, stirring and crystallizing 2-3 hours,
Filtering, filter cake is washed with a small amount of 50% ethanol solution, less than 70 DEG C drying, must be hydrogenated with thing 89.6g, HPLC content 99.4%, weight
Measure total recovery 89.6%.
D, Mestanlone preparation
In a 1000ml there-necked flask, add under 100g hydrogenation things, 600ml ethanol, stirring at normal temperature and add the salt of 100g 20%
Acid, is slowly ramped to 50-55 DEG C, back flow reaction 6-8 hours, TLC detection reaction ends after having reacted, add 40g 50% burning
Alkali lye is neutralized to PH6.5, then vacuum distillation, reclaims about 90-95% ethanol, then adds 600 ml running water, be cooled to 10
~15 DEG C, stirring and crystallizing 2-3 hours, filtering is washed to below neutrality, 70 DEG C of filter cake and dried, obtains Mestanlone crude product 89.6g.
Disposing mother liquor solvent and crude product are applied mechanically.Above-mentioned Mestanlone crude product is dissolved in 500ml alcohol, 5g activated carbons is added, heats up back
Decolouring 1-1.5 hours is flowed, is filtered while hot, 100ml ethanol wash filter cakes, washing lotion and filtrate merge, normal pressure concentration and recovery about 90%
Alcohol, is then cooled to -5-0 DEG C, freezing crystallization 2-3 hours, filtering, a small amount of ethanol wash of filter cake, less than 70 DEG C drying are obtained
Mestanlone 82.5g, yield 82.5%, 192.5-194.0 DEG C of fusing point, HPLC contents 99.7%；Filtrate is covered for lower batch of refined work
In skill.
Embodiment two
A, etherate preparation
In a 1000ml there-necked flask, 100g 4AD, 600ml dichloromethane, 80ml triethyl orthoformates, 2g are added to toluene
Sulfonic acid, is incubated in 20-25 DEG C of stirring reaction 12~16 hours, TLC detection reaction ends, after react, addition 3ml pyridines are stirred
Mix 20-25 minutes and neutralize acid, be concentrated under reduced pressure, reclaim dichloromethane, cooling adds 100ml ethanol, be then cooled to system-
5-0 DEG C, stirred crystallization 2~3 hours, suction filtration, a small amount of ethanol washing, washing lotion and filtrate merge, and recycling design and crude product are applied mechanically；Filter
Dried below 70 DEG C of cake, obtain etherate 100.2g, HPLC content 99.4%, weight yield 100.2%.
B, grignard thing preparation
In a 2000ml there-necked flask, 20g metals magnesium chips, 500mlTHF are added, 40-45 DEG C is warming up to, lead to nitrogen displacement
Afterwards, chloromethanes, stirring reaction 8~10 hours are slowly passed through, until metal reactive magnesium is complete.After having reacted, stopping is passed through chloromethane
RMgBr is just obtained after alkane, logical nitrogen displacement, it is standby.The above-mentioned etherates of 100g are added in another 1000ml reaction bulb,
800ml toluene is added, being stirred at room temperature makes its dissolving complete, and this etherate solution then is added into a 1000ml dropping funel
In, and this dropping funel is placed on above-mentioned 2000ml there-necked flasks, above-mentioned standby RMgBr is incubated in 40-45 DEG C, so
The toluene solution of above-mentioned etherate is slowly added dropwise afterwards, drips off within about 1-1.5 hours, and continues insulation reaction 3-4 hours, TLC detections,
Until grignard reaction completely, after having reacted, is slowly added dropwise to 350ml 10% hydrochloric acid, in 40-45 DEG C of insulated and stirred, acidolysis is anti-
Answer 3-4 hours, TLC detections, after acidolysis reaction is complete, the soda bath of addition 10% is neutralized to the PH about 6.5 of system, then will
System, which is concentrated under reduced pressure, reclaims about 90-95% solvent THF and toluene, slightly cools down, adds 500ml running water, cool to 5-10
DEG C, stirred crystallization 2~3 hours, suction filtration is washed, and is dried below 70 DEG C of filter cake, is obtained grignard thing 101.6g, HPLC content 99.6%,
Weight yield 101.6%.
C, the preparation for being hydrogenated with thing
In a 2000ml there-necked flask, 100g grignard thing, 1000ml glacial acetic acid are added, 15g 5% palladium carbon is added after dissolving,
40-45 DEG C is warming up to, after nitrogen displacement, hydrogen is passed through, insulated and stirred is reacted 8~10 hours, TLC detection reaction ends, instead
After having answered, nitrogen displacement, nitrogen press filtration while hot, 50ml glacial acetic acid washing, filter cake send producer to reclaim；Washing lotion and filtrate merge, and subtract
Pressure concentration, reclaims glacial acetic acid and applies mechanically.Residual night adds 600ml running water elutriations, filtering, obtains solid hydrogenation thing crude product.By above-mentioned solid
Hydrogenation thing crude product is directly added in 800ml alcohol, and heating dissolves it, adds 5g activated carbons, and flow back decolouring 1-1.5 hours,
Filter while hot, filter cake about 80ml alcohol foam washings, merging filtrate and washing lotion, normal pressure is concentrated into about 85% alcohol of recovery, then adds
50ml pure water, continues to steam about 100ml 50-60% containing ethanol solvent, then system is cooled into 5-10 DEG C, stirring and crystallizing 2-3
Hour, filtering, filter cake is washed with a small amount of 50% ethanol solution, less than 70 DEG C drying, must be hydrogenated with thing 87.8g, HPLC content
99.6%, weight total recovery 87.8%.
D, Mestanlone preparation
In a 1000ml there-necked flask, add under 100g hydrogenation thing, 600ml glacial acetic acid, stirring at normal temperature and add the hydrogen of 50g 40%
Bromic acid, is slowly ramped to 50-55 DEG C, back flow reaction 6-8 hours, TLC detects reaction end, after having reacted, vacuum distillation, reclaims
About 90-95% glacial acetic acid, then adds in 20g 50% soda bath and PH is to about 6.5, add 600 ml running water, drop
Temperature is to 10~15 DEG C, and stirring and crystallizing 2-3 hours, filtering is washed to below neutrality, 70 DEG C of filter cake and dried, obtains Mestanlone crude product
87.9g.Disposing mother liquor solvent and crude product are applied mechanically.Above-mentioned Mestanlone crude product is dissolved in 500ml alcohol, 5g activated carbons are added,
Temperature rising reflux decolouring 1-1.5 hours, is filtered while hot, 100ml ethanol wash filter cakes, and washing lotion and filtrate merge, normal pressure concentration and recovery
About 90% alcohol, is then cooled to -5-0 DEG C, freezing crystallization 2-3 hours, filtering, a small amount of ethanol wash of filter cake, less than 70 DEG C
Drying, obtains Mestanlone 80.8g, yield 80.8%, 193.5-194.0 DEG C of fusing point, HPLC contents 99.8%；Filtrate is covered for lower batch
In process for refining.
Embodiment three
A, etherate preparation
In a 1000ml there-necked flask, 100g 4AD, 200ml ethanol, 80ml triethyl orthoformates, 2g 98% sulphur are added
Acid, is incubated in 20-25 DEG C of stirring reaction 12~16 hours, TLC detection reaction ends after react, add 3ml pyridines, stirred
Neutralize acid within 20-25 minutes, system is then cooled to -5-0 DEG C, stirred crystallization 2~3 hours, suction filtration, a small amount of ethanol washing is washed
Liquid and filtrate merge, and recycling design and crude product are applied mechanically；Dried below 70 DEG C of filter cake, obtain etherate 100.8g, HPLC content
99.0%, weight yield 100.8%.
B, grignard thing preparation
In a 2000ml there-necked flask, 20g metals magnesium chips, 500ml ether are added, 38-40 DEG C is warming up to, lead to nitrogen displacement
Afterwards, iodomethane, stirring reaction 8~10 hours is slowly added dropwise, until metal reactive magnesium is complete.After having reacted, stop that iodine first is added dropwise
RMgBr is just obtained after alkane, logical nitrogen displacement, it is standby.The above-mentioned etherates of 100g are added in another 1000ml reaction bulb,
800mlTHF is added, being stirred at room temperature makes its dissolving complete, and this etherate solution then is added into a 1000ml dropping funel
In, and this dropping funel is placed on above-mentioned 2000ml there-necked flasks, above-mentioned standby RMgBr is incubated in 40-42 DEG C, so
The THF solution of above-mentioned etherate is slowly added dropwise afterwards, drips off within about 1-1.5 hours, and continues insulation reaction 3-4 hours, TLC detections,
Until grignard reaction completely, after having reacted, is slowly added dropwise to 350ml 10% hydrochloric acid, in 40-45 DEG C of insulated and stirred, acidolysis is anti-
Answer 3-4 hours, TLC detections, after acidolysis reaction is complete, the soda bath of addition 10% is neutralized to the PH about 6.5 of system, then will
System, which is concentrated under reduced pressure, reclaims about 90-95% solvent ether and THF, slightly cools down, adds 500ml running water, cool to 5-10
DEG C, stirred crystallization 2~3 hours, suction filtration is washed, and is dried below 70 DEG C of filter cake, is obtained grignard thing 103.5g, HPLC content 99.2%,
Weight yield 103.5%.
C, the preparation for being hydrogenated with thing
In a 2000ml there-necked flask, 100g grignard thing, 1000ml ethyl acetate are added, 15g 5% palladium is added after dissolving
Carbon, is warming up to 40-45 DEG C, after nitrogen displacement, is passed through hydrogen, and insulated and stirred is reacted 8~10 hours, TLC detection reaction ends,
After having reacted, nitrogen displacement, nitrogen press filtration while hot, 50ml ethanol washing, filter cake send producer to reclaim；Washing lotion and filtrate merge, and subtract
Pressure concentration, reclaims ethyl acetate and applies mechanically.Residual night adds 600ml running water elutriations, filtering, obtains solid hydrogenation thing crude product.Will be above-mentioned solid
Body hydrogenation thing crude product is directly added in 800ml alcohol, and heating dissolves it, adds 5g activated carbons, and backflow decolouring 1-1.5 is small
When, filter while hot, filter cake about 80ml alcohol foam washings, merging filtrate and washing lotion, normal pressure is concentrated into about 85% alcohol of recovery, then
50ml pure water is added, continues to steam about 100ml 50-60% containing ethanol solvent, then system is cooled to 5-10 DEG C, stirring analysis
It is brilliant 2-3 hours, filtering, filter cake washs with a small amount of 50% ethanol solution, and less than 70 DEG C dry, and must be hydrogenated with thing 88.5g, and HPLC contains
Amount 99.5%, weight total recovery 88.5%.
D, Mestanlone preparation
In a 1000ml there-necked flask, add under 100g hydrogenation thing, 600ml chloroforms, stirring at normal temperature and add 20g to toluene sulphur
Acid, is slowly ramped to 50-55 DEG C, back flow reaction 6-8 hours, TLC detection reaction ends after having reacted, add 10g 50% burning
Alkali lye is neutralized to PH about 6.5, and then vacuum distillation reclaims about 90-95% chloroform, then adds 600 ml running water, be cooled to
10~15 DEG C, stirring and crystallizing 2-3 hours, filtering is washed to below neutrality, 70 DEG C of filter cake and dried, obtains Mestanlone crude product
88.6g.Disposing mother liquor solvent and crude product are applied mechanically.Above-mentioned Mestanlone crude product is dissolved in 500ml alcohol, 5g activated carbons are added,
Temperature rising reflux decolouring 1-1.5 hours, is filtered while hot, 100ml ethanol wash filter cakes, and washing lotion and filtrate merge, normal pressure concentration and recovery
About 90% alcohol, is then cooled to -5-0 DEG C, freezing crystallization 2-3 hours, filtering, a small amount of ethanol wash of filter cake, less than 70 DEG C
Drying, obtains Mestanlone 82.8g, yield 82.8%, 192.5-193.5 DEG C of fusing point, HPLC contents 99.5%；Filtrate is covered for lower batch
In process for refining.
Claims (5)
1. the preparation method of Mestanlone, using 4AD as raw material, triethyl orthoformate makees reagent, is etherified by 3 alkene of 4AD,
Acid catalysis prepares etherate 3- ethyoxyls-androstane -3,5- diene -17- ketone in organic solvent；It is characterized in that, the etherate is having
In machine solvent, 17 ketone grignards, simultaneously sour water solves grignard thing 3- ethyoxyl -17a- first with the addition of methyl-magnesium-halide RMgBr
Base-androstane -3,5- diene -17b- alcohol；The grignard thing uses palladium carbon catalytic hydrogenation in organic solvent, obtain hydride 3- ethyoxyls-
17a- methyl-androst -17- alcohol；By this hydride, acid-catalyzed hydrolysis obtains Mestanlone crude product in organic solvent, then with alcohol,
Decolorizing with activated carbon is refining to obtain Mestanlone.
2. the preparation method of Mestanlone as claimed in claim 1, it is characterized in that, concrete operation step is as follows：
A, etherate preparation
4AD is dissolved in organic solvent, with triethyl orthoformate under acid catalysis, in 20-50 DEG C of stirring reaction 12-16 hours,
After having reacted, add weak base and be neutralized to pH7-7.5, etherate 3- ethyoxyls-androstane -3,5 diene -17- ketone is obtained after processing, its
HPLC content 98.5-99.5%, weight yield 100-102%；
B, grignard thing preparation
Organic solvent tetrahydrofuran or ether, metal magnesium chips are added in reaction bulb, 30-80 DEG C is warming up to, is then slowly added dropwise
Or methyl halogenated alkane is poured, until metal magnesium chips reacts disappearance completely, RMgBr is made, 10 DEG C or so of cooling is standby；Another
In one reaction bulb, above-mentioned etherate is dissolved in organic solvent, then this etherate solution be added dropwise to the grignard made
Grignard addition reaction is brought it about in reagent, after dripping, continues insulation reaction 2-3 hours, until TLC shows that raw material has reacted
Entirely；Then, aqueous acid is slowly added dropwise and is incubated hydrolysis again 3-4 hours, TLC determines reaction end, then is slowly added into alkali lye
Be neutralized to pH6-7, then the recovery organic solvent that is concentrated under reduced pressure, finally add water crystallization, filtration drying, obtain grignard thing 3- ethyoxyls-
17a- methyl-androst -3,5- diene -17b- alcohol, its HPLC content 97.5%-98.5%, weight yield 100-105%；
C, hydride preparation
Above-mentioned grignard thing is dissolved in organic solvent, 5% palladium carbon is added, with hydrogen is passed through after nitrogen displacement air, is warming up to
30-60 DEG C is reacted 8-10 hours, after having reacted, emptying, and nitrogen press filtration is used while hot, and a small amount of solvent washing, filter cake send producer to reclaim,
Washing lotion and filtrate merge, and reclaim elutriation after organic solvent, obtain solid；This solid wet product is directly tied again with alcohol, activated carbon decolorizing
Crystalline substance, obtains the ethyoxyl -17a- methyl-androst -3- alkene -17- alcohol of hydride 3, HPLC contents more than 99.0%, weight yield 85-90%；
D, Mestanlone preparation
Above-mentioned hydrogenation thing is dissolved in organic solvent, acid catalyst is added, 30-100 DEG C is warming up to, reacts 6-8 hours, has reacted
Afterwards, add alkali lye and be neutralized to pH6-7, then reclaim organic solvent, cool elutriation, obtains Mestanlone crude product.
3. above-mentioned crude product is recrystallized with alcohol, activated carbon decolorizing, Mestanlone, 192.5-194.0 DEG C of fusing point, content ＞ are obtained
99%, yield 80-85%.
4. the preparation method of Mestanlone as claimed in claim 1, it is characterized in that,
A walks the 1-2 kinds that the organic solvent is selected in dichloromethane, toluene, methanol, ethanol；Reaction acid catalyst choosing used
With one kind in hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, p-methyl benzenesulfonic acid, oxalic acid；Neutralize weak base used and select sodium carbonate or pyridine；
Reaction temperature is 20-50 DEG C；Weight proportion between reactant is, 4AD：Triethyl orthoformate：Acid=1：0.5-1.0 :0.01-
0.05；Proportioning between reactant and solvent is, 4AD：Organic solvent=1：2-8；
B walks the organic solvent, from the 1-2 kinds in tetrahydrofuran derivatives cyclic ethers, chloroform, toluene, methyl ether, ether；Grignard
Reaction methyl halogenated alkane used, from bromomethane or chloromethanes or iodomethane；Acid catalyst used in hydrolysis from hydrochloric acid,
One kind in sulfuric acid, phosphoric acid, p-methyl benzenesulfonic acid, oxalic acid；Neutralize alkali lye used and select caustic soda or sodium carbonate or ethamine；Grignard reaction
Reaction temperature with hydrolysis is 30-80 DEG C；Quality proportioning between reactant is, etherate：Magnesium：Alkyl halide：Acid=1：
0.08-0.25: 0.2-0.5：0.2-0.5；Proportioning between reactant and solvent is, etherate：RMgBr prepares organic molten
Agent：Grignard reaction organic solvent=1g：2-8ml： 5-15ml；
C walks the organic solvent, from one kind in ethanol, acetic acid, ethyl acetate, tetrahydrofuran, acetic acid, acetone；Catalyst
Be 5% palladium carbon, 30-60 DEG C of reaction temperature；Weight proportion between reactant is, grignard thing：Palladium carbon：Hydrogen=1：0.05-0.25：
0.01-0.15；Proportioning between reactant and solvent is, grignard thing：Organic solvent=1g：5-20ml；
D walks the organic solvent, from acetic acid, alcohol, toluene, chloroform, formic acid, acetic acid, ethanol, isopropanol, the tert-butyl alcohol
It is a kind of；The acid is from one kind in hydrochloric acid, hydrobromic acid, perchloric acid, sulfuric acid or acetic acid, p-methyl benzenesulfonic acid, and reaction temperature is
30-100℃；Weight proportion between reactant is to be hydrogenated with thing：Acid=1：0.15-0.25；Proportioning between reactant and solvent is, plus
Hydrogen thing：Organic solvent=1g：4-10ml.
5. the preparation method of Mestanlone as claimed in claim 1, it is characterized in that,
A, etherate preparation, reaction acid catalyst used is p-methyl benzenesulfonic acid, neutralizes weak base used
It is pyridine, reaction temperature is that the weight proportion between 20-30 DEG C, reactant is, 4AD：Triethyl orthoformate：Acid=1: 0.8
:0.02；
B, grignard thing preparation, the organic solvent are tetrahydrofurans, and methyl halogenated alkane used in grignard reaction is bromomethane, hydrolysis
Reaction acid catalyst used is hydrochloric acid, and it is soda bath to neutralize alkali lye used,
The reaction temperature DEG C of grignard reaction and hydrolysis is that the quality proportioning between 40-60 DEG C, reactant is, etherate：Magnesium：Halo
Alkane：Acid=1: 0.20: 0.35 :0.35；Proportioning between reactant and solvent is, etherate：RMgBr prepares organic solvent：
Grignard reaction organic solvent is 1g: 5ml: 8ml;
C, hydride preparation, described organic solvent are ethanol or acetic acid, and catalyst is 5% palladium carbon, reaction temperature 40-45
℃；Weight proportion between reactant is, grignard thing：Palladium carbon：Hydrogen=1: 0.15 :0.10；Proportioning between reactant and solvent
It is：Grignard thing：Organic solvent is 1g：10ml；
D, Mestanlone preparation, described organic solvent are acetic acid or alcohol, and the acid is hydrochloric acid,
Weight proportion between 50-60 DEG C of reaction temperature, reactant is to be hydrogenated with thing：Acid=1:0.2, matching somebody with somebody between reactant and solvent
Than being, thing is hydrogenated with：Organic solvent is 1g：6ml.
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| CN109369760A (en) * | 2018-12-18 | 2019-02-22 | 湖南科瑞生物制药股份有限公司 | A method of preparing danabol |
| CN109369761A (en) * | 2018-12-18 | 2019-02-22 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of danabol |
| CN109503692A (en) * | 2018-12-05 | 2019-03-22 | 华中药业股份有限公司 | A kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane |
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| CN109503692A (en) * | 2018-12-05 | 2019-03-22 | 华中药业股份有限公司 | A kind of synthetic method of -17 beta-hydroxy -3- ketone of -17 Alpha-Methyl of androstane |
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| CN115286672A (en) * | 2022-08-16 | 2022-11-04 | 黄冈人福药业有限责任公司 | Preparation method of nandrolone |
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