CN106397520A - Preparation method of methyltestosterone - Google Patents
Preparation method of methyltestosterone Download PDFInfo
- Publication number
- CN106397520A CN106397520A CN201610800810.4A CN201610800810A CN106397520A CN 106397520 A CN106397520 A CN 106397520A CN 201610800810 A CN201610800810 A CN 201610800810A CN 106397520 A CN106397520 A CN 106397520A
- Authority
- CN
- China
- Prior art keywords
- acid
- grignard
- organic solvent
- etherate
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention provides a preparation method of methyltestosterone. 4AD short for 4-androstenedione is taken as a raw material, and etherate is synthesized firstly as follows: 4AD and triethyl orthoformate are subjected to an acid catalyzed reaction in a low-carbon alcohol organic solvent, and 3-ethoxy-androst-3,5-diene-17-one as the etherate is obtained; then a Grignard product is synthesized as follows: a Grignard reagent methyl magnesium halide and the etherate are placed in an organic solvent, the 17-position ketone group of the etherate and the Grignard reagent are subjected to addition, and the Grignard product 3-ethoxy-17a-methyl-androst-3,5-diene-17-ol is obtained through hydrolysis; then the Grignard product is subjected to an acid catalyzed hydrolysis in an organic solvent, and crude methyltestosterone is obtained; the crude methyltestosterone is decolorized by activated carbon in C4-below low-carbon alcohol and recrystallized, the methyltestosterone is obtained, HPLC content is 99.0%-99.5%, and the total yield of synthesis weight is 75%-78%. According to the method, the raw materials are widely sourced, the process is simple and convenient to operate, the product yield is high, the purity is good, the solvent recovery rate is high in reaction and technological processing, and the method is economical and environment-friendly.
Description
Technical field
The invention belongs to the fabricating technology of steroid hormone pharmaceutical intermediate is and in particular to arrive a kind of androgen drug
The preparation method of methyl testosterone.
Background technology
Methyl testosterone is a kind of androgen drug, is clinically primarily to facilitate sending out of male genitals and secondary sexual characteristicss
Educate and maintain its normal function, be also used for dysfunctional uterine hemorrhage and the animal migration breast carcinoma of women, simultaneously can be used for synthesizing
Other senior androgen drugs such as propanoic acid methyl testosterone, market is huge.The conventional production methods of methyl testosterone, are from potato
Diosgenin is extracted, through protection, oxicracking, elimination, the key intermediate acetic acid gestation diene alcohol ketone of acquisition in Chinese yam plant
（Abbreviation diene）For raw material, through six-step processes such as oximate, Beckmann rearrangement, acid hydrolysis, grignard reaction, basic hydrolysiss, Ovshinsky oxidations
It is obtained, its synthetic route is shown in accompanying drawing 1.The wherein extraction of diosgenin, oxicracking, Beckmann rearrangement, acid, macromolecule alkali for hydrolysis
Etc. technique, generation waste water is more, not disposable, easily pollutes environment；The Ovshinsky oxidation technology adopting in production, need to be steamed with water vapour
Evaporate, water consumption power consumption is big.Importantly, with wild Rhizoma Dioscoreae plant resourceses increasingly depleted, and artificial growth Rhizoma Dioscoreae plant, also because
Manually, the increasingly rising of the planting cost such as chemical fertilizer, leads to the production cost of Saponin, diene to be doubled and redoubled, causes methyl testosterone
Production cost increase substantially with the market price, already significant impact was created to global methyl testosterone pharmaceutical market.
Content of the invention
It is an object of the invention to provide a kind of preparation method of new methyl testosterone, overcome traditional processing technology synthesis former
Expect expensive, many deficiencies such as synthetic route length, complex operation, environmental protection treatment hardly possible, production cost height.Change five steps and synthesize three steps
Synthesis, expands raw material sources, reduces environmental pollution, reduces production cost.
The technical scheme is that：The preparation method of methyl testosterone, that is, with 4-AD（Abbreviation 4AD）For former
Material, first synthesizes etherate, secondary synthesis grignard thing, resynthesis methyl testosterone；
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 grignard thing, are with 17 in the organic solution of Grignard reagent methyl-magnesium-halide and the etherate dissolving in organic solvent
Position ketone group addition simultaneously hydrolyzes to obtain grignard thing 3- ethyoxyl -17a- methyl-androst -3,5- diene -17- alcohol；
C, synthesizing methyl Testosterone, are that acid-catalyzed hydrolysis obtain methyl testosterone by grignard thing in organic solvent.
Further, the concrete operations of its synthesis 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 0.02g weak base to be neutralized to pH 7～7.5, further work-up, obtain etherate 3- second
Epoxide-androstane -3,5 diene -17- ketone, its HPLC content 98.5～99.5%, weight yield 100～102%；
B, the synthesis of grignard thing：Magnesium powder, organic solvent are added to reactor stirring, temperature control, to 25-55 DEG C, is slowly added into
Methyl halogenated alkane, reacts 4-6 hour, until magnesium powder is wholly absent, obtains Grignard reagent standby；Again above-mentioned etherate is dissolved in
In machine solvent, stirring, temperature control to 40-60 DEG C, the slowly above-mentioned Grignard reagent got ready of Deca, about 1-1.5 hour drips off, then is incubated
React 2～3 hours in 40～60 DEG C, TLC confirms reaction end, after having reacted, more slowly Deca acid, hydrolyze 2-3 hour, hydrolysis
After complete, point water, washing, organic layer concentrating under reduced pressure reclaims organic solvent, then with ethanol, activated carbon decolorizing recrystallization, obtains grignard
Thing 3 ethyoxyl -17a methyl-androst 3,5,-diene -17- alcohol, HPLC content more than 99.0%, weight yield 90～95%.
C, the synthesis of methyl testosterone：Above-mentioned grignard thing is dissolved in organic solvent, stirring, be incubated at 40～80 DEG C
Slowly Deca acid, reacts 10～12 hours, and TLC confirms reaction end, and after having reacted, with liquid adjusting PH with base to 6.8 ~ 7.2, recovery has
Machine solvent, elutriation of lowering the temperature, obtain methyl testosterone crude product；HPLC content 97.0-98.5%, weight yield 85.5-88.5%；Crude product is molten
Enter in below C4 low-carbon alcohols, add activated carbon, be heated to reflux 1.5-2.0 hour, slightly cool down, filtered while hot, filter cake is with being equivalent to
Collection after the low-carbon alcohols washing of the grignard that feeds intake thing 0.5-1 part weight is processed, and liquid and filtrate merge, and normal pressure is concentrated into recovery 88-90%
Solvent, then stop concentrating, be cooled to -5-0 DEG C, stirring and crystallizing 3-4 hour, filter, filtrate recycling design applied mechanically with mother solution material,
Dry below 100 DEG C of filter cake, obtain methyl testosterone product, 162～167 DEG C of fusing point, HPLC content 99.0-99.5%, this step yield
80-82%.
Organic solvent described in above-mentioned etherate synthesis, including dichloromethane, toluene, below C4 low-carbon alcohols such as methanol, second
Alcohol, preferably ethanol；Reaction acid catalyst used includes mineral acid example hydrochloric acid, sulphuric acid, phosphoric acid, or organic acid such as acetic acid, right
Toluenesulfonic acid, oxalic acid, preferably p-methyl benzenesulfonic acid, catalytic effect is good；Weak base used by neutralization includes sodium carbonate or pyridine, reaction
20～50 DEG C of temperature, best 20～30 DEG C；The weight proportion of reactant is, 4AD：Triethyl orthoformate：Acid=1：0.5～1.0:
0.01～0.05；Preferably 1：0.8：0.02；Proportioning between reactant and solvent is, 4AD：Organic solvent=1g：2～8ml, be
It is 1g well::6～8ml.
Grignard thing synthesizes the organic solvent of described grignard reaction, including toluene, benzene, chloroform, oxolane, dioxane,
Preferably toluene；The organic solvent of Grignard reagent preparation includes various ethers and cyclic ethers, such as ether, oxolane, preferably tetrahydrochysene
Furan；The methyl halogenated alkane of reagent of Grignard reagent preparation, including chloromethanes, bromomethane, iodomethane, preferably bromomethane；Hydrolysis
Acid inclusion organic acid such as acetic acid, p-methyl benzenesulfonic acid or mineral acid example hydrochloric acid, sulphuric acid used, preferably hydrochloric acid is inexpensive；Lattice
Family name's reagent preparation reaction temperature is 25～55 DEG C, best 40～45 DEG C；The reaction temperature of grignard reaction and hydrolysis is 40～
60 DEG C, preferably 50～55 DEG C, the weight proportion between reactant is, etherate：Magnesium：Halide：Grignard reagent solvent=1：
0.2～0.5:0.8～1.5：2～5, preferably 1：0.35：1.2:3.5；Proportioning between reactant and solvent is：Etherate：Instead
Answer organic solvent=1g：4～8ml, preferably 1g：5ml.
Organic solvent used by methyl testosterone is prepared in above-mentioned grignard thing hydrolysis, including toluene, acetone, below C4 unitary fat
Acid such as formic acid, acetic acid, below C4 low-carbon alcohols such as methanol, ethanol, isopropanol, the tert-butyl alcohol, preferably acetic acid or ethanol, reaction effect
Good, convenient recovery；Described acid includes inorganic acid example hydrochloric acid, sulphuric acid etc., or organic acid such as trifluoroacetic acid, p-methyl benzenesulfonic acid etc.,
Preferably hydrochloric acid, inexpensive environmental protection；40～80 DEG C of reaction temperature, best 60～65 DEG C；Weight proportion between reactant is：Grignard
Thing：Acid=1：0.6～1.2, preferably 1：0.8；Proportioning between reactant and solvent is, grignard thing：Organic solvent=1g：4-6ml,
Preferably 1g：5ml.
The invention has the beneficial effects as follows：Relatively make the traditional method of raw material with diosgenin, methyl is prepared for raw material with 4AD
Testosterone, raw material sources are extensive, process economicses environmental protection, and production cost declines to a great extent.Synthetic route is short, simple process environmental protection, produces
Product high income, three-step reaction synthesizes total recovery 75-78%.Quality is good, is calculated with the current prices of raw materials, and raw materials for production cost drops
Low 20-25%；Solvent used in technique, recyclable recycled, both economical, and environmental protection, it is very beneficial to industrialized production.
Brief description
Fig. 1 is traditional methyl testosterone synthetic route chart；
Fig. 2 is methyl testosterone synthetic route chart of the present invention.
Specific embodiment
In order to illustrate in greater detail main points and the spirit of the present invention, name three embodiments and be explained：
Embodiment one：
A, the preparation of etherate
In a 1000ml there-necked flask, add 100g 4AD, 200ml ethanol, 80ml triethyl orthoformate, 2g is to toluene sulphur
Acid, is incubated in 20～25 DEG C of stirring reactions 12～16 hours, TLC detects reaction end, adds 3ml pyridine after react, stirs
Then system is cooled to -5～0 DEG C by the neutralization acid of 20-25 minute, stirred crystallization 2～3 hours, sucking filtration, and a small amount of washing with alcohol is washed
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 content
99.2%, weight yield 101.6%.
B, the preparation of grignard thing
In a 1000ml there-necked flask, add 35g magnesium powder, 350ml oxolane, stirring, be incubated and be passed through in 45-50 DEG C
120g bromomethane, continues stirring reaction 4～6 hours after having led to, until magnesium powder disappears substantially, obtains Grignard reagent standby；Another
In individual 1000ml there-necked flask, add 100g etherate, 500ml toluene, stirring is warming up to 50～55 DEG C, and slowly Deca is above-mentioned gets ready
Grignard reagent solution, about 1-1.5 hour drips off, and is further continued for insulated and stirred and reacts 2～3 hours, TLC detects reaction end, instead
After having answered, slowly Deca 2N hydrochloric acid is 2-3 to pH, continues hydrolysis 2-3 hour after dripping off, and TLC detection hydrolysis completely, is reacted
It is cooled to 20-25 DEG C after complete, point water, 200x2 water washing from the beginning, it is evaporated to closely dry, recycling design processing is applied mechanically.Exist again
600ml ethanol is added, heating makes it dissolve, and adds 5g activated carbon, reflux decolour 1～1.5 hour, mistake while hot in above-mentioned residual night
Filter, filter cake 80ml ethanol foam washing, merging filtrate and washing liquid, normal pressure is concentrated into recovery about 85% ethanol, is subsequently adding 500ml pure
Water purification, continues to steam the solvent that about 150ml contains ethanol 50-60%, then system is cooled to 5～10 DEG C, stirring and crystallizing 2～3 is little
When, filter, filter cake is washed with a small amount of 50% ethanol solution, dries for less than 70 DEG C, obtains grignard thing 94.6g, HPLC content
99.2%, weight yield 94.6%.
C, the preparation of methyl testosterone
In a 1000ml there-necked flask, add 100g grignard thing, 500ml toluene, stirring, be slowly ramped to 60～65 DEG C, drip
Plus 30% hydrochloric acid solution 240ml, drip off within about 1.5～2 hours, drip off rear insulation reaction 4～5 hours, after having reacted, be cooled to 20-
25 DEG C, point water, 2x200ml water washing from the beginning, then vacuum distillation, reclaims about 90 ~ 95% toluene, is 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 methyl testis below 70 DEG C of filter cake
Ball element crude product 87.5g, HPLC content 98.5%, yield 87.5%.Above-mentioned crude product is dissolved in 500ml ethanol, adds 5g activated carbon,
It is heated to reflux 1.5-2 hour, be cooled to 55-60 DEG C, filtered while hot, filter cake about 80ml ethanol foam washing, merging filtrate and washing liquid,
Normal pressure is concentrated into recovery about 88-90% ethanol, then system is cooled to -5～0 DEG C, and stirring and crystallizing 2～3 hours filters, and filtrate is returned
Receive solvent to apply mechanically with mother solution material, filter cake is washed with a small amount of 50% ethanol solution, dries for less than 70 DEG C, obtains methyl testosterone
81.6g, HPLC content 99.2%, weight yield 81.6%.
Embodiment two：
A, the preparation of etherate
In a 1000ml there-necked flask, add 100g 4AD, 600ml dichloromethane, 80ml triethyl orthoformate, 2g is to toluene
Sulfonic acid, is incubated in 20～25 DEG C of stirring reactions 12～16 hours, TLC detects reaction end, and after react, addition 3ml pyridine, stirs
Mix neutralization acid in 20～25 minutes, concentrating under reduced pressure, reclaim dichloromethane, cooling, add 100ml ethanol, then system is cooled to-
5～0 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；
Dry below 70 DEG C of filter cake, obtain etherate 100.2g, HPLC content 99.4%, weight yield 100.2%.
B, the preparation of grignard thing
In a 1000ml there-necked flask, add 35g magnesium powder, 350ml ether, stirring, be incubated and be passed through 120g chlorine in 35-40 DEG C
Methane, continues stirring reaction 4～6 hours after having led to, until magnesium powder disappears substantially, obtains Grignard reagent standby；At another
In 1000ml there-necked flask, add 100g etherate, 500ml toluene, stirring is warming up to 50～55 DEG C, slowly Deca is above-mentioned gets ready
Grignard reagent solution, about 1-1.5 hour drips off, and is further continued for insulated and stirred and reacts 2～3 hours, after TLC detection reaction end, slowly
Slow Deca 2N hydrochloric acid, to pH 2-3, continues hydrolysis 2-3 hour after dripping off, TLC detection hydrolysis is complete, according to reality after having reacted
Test the processing method of example one related content, obtain grignard thing 91.6g, HPLC content 99.5%, weight yield 91.6%.
C, the preparation of methyl testosterone
In a 1000ml there-necked flask, add 100g grignard thing, 500ml ethanol, stirring, be slowly ramped to 60～65 DEG C, drip
The hydrobromic acid solution 240ml plus 40%, drips off for about 1.5～2 hours, after dripping off, insulation reaction 4～5 hours, and after having reacted, cooling
To 20-25 DEG C, add liquid adjusting PH with base to 6.5-7.5, then vacuum distillation, reclaim the ethanol of 90-95%, be subsequently adding 600 ml
Tap water, is cooled to 10～15 DEG C, stirring and crystallizing 2-3 hour, filters, is washed to neutrality, dries, obtain methyl below 70 DEG C of filter cake
Testosterone crude product 87.0g, HPLC content 98.5%, yield 87.0%.By above-mentioned crude product according to experimental example one associative operation recrystallization,
Obtain methyl testosterone 80.8g, HPLC content 99.4%, weight yield 80.8%.
Embodiment three
A, the preparation of etherate
In a 1000ml there-necked flask, add 100g 4AD, 200ml ethanol, 80ml triethyl orthoformate, be passed through HCl gas
2g, airtight, it is incubated in 20-25 DEG C of stirring reaction 12～16 hours, TLC detects reaction end, after react, addition 3ml pyrrole
Pyridine, stirring neutralization acid in 20～25 minutes, then system is cooled to -5～0 DEG C, stirred crystallization 2～3 hours, sucking filtration, Shao Liangyi
Alcohol washs, 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 grignard thing
In a 1000ml there-necked flask, add 35g magnesium powder, 350ml oxolane, stirring, be incubated and be passed through in 35-40 DEG C
120g bromomethane, after having led to, continues stirring reaction 4～6 hours, until magnesium powder disappears substantially, obtains Grignard reagent standby；Another
In individual 1000ml there-necked flask, add 100g etherate, 500ml oxolane, stirring is warming up to 50～55 DEG C, and slowly Deca is above-mentioned
The grignard reagent solution got ready, about 1-1.5 hour drips off, and is further continued for insulated and stirred and reacts 2～3 hours, TLC detects reaction end
Afterwards, slowly Deca 2N hydrochloric acid, to pH 2-3, continues hydrolysis 2-3 hour after dripping off, and TLC detection hydrolysis is complete, after having reacted,
It is cooled to 20-25 DEG C, dropping liquid adjusting PH with base 7.0-7.5, the then oxolane of concentrating under reduced pressure recovery 90-95%, then be cooled to
20-25 DEG C, add 500ml tap water, stirring and crystallizing, obtain grignard thing crude product, crude product ethanol recrystallization, obtain grignard thing 94.6g,
HPLC content 99.2%, weight yield 94.6%.
C, the preparation of methyl testosterone
In a 1000ml there-necked flask, add 100g grignard thing, 500ml toluene, stirring, be slowly ramped to 60～65 DEG C, drip
The p-methyl benzenesulfonic acid solution 240ml plus 50%, drips off for about 1.5～2 hours, after dripping off, insulation reaction 5～6 hours, and after having reacted,
According to the disposal methods of experimental example one related content, obtain methyl testosterone crude product 87.2g, HPLC content 98.0%, yield
87.2%.By above-mentioned crude product according to experimental example one same operation recrystallization, obtain methyl testosterone 80.2g, HPLC content 99.5%, weight
Amount yield 80.2%.
Claims (4)
1. the preparation method of methyl testosterone, that is, with 4-AD（Abbreviation 4AD）For raw material it is characterised in that：Anti- through three steps
Answer synthesizing methyl Testosterone；
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 grignard thing, are to be dissolved in organic solvent with Grignard reagent methyl-magnesium-halide and above-mentioned etherate, make in etherate
17 ketone groups and Grignard reagent addition, and hydrolyze to obtain grignard thing 3- ethyoxyl -17a- methyl-androst -3,5- diene -17- alcohol；
C, synthesizing methyl Testosterone, are that acid-catalyzed hydrolysis obtain methyl testosterone by grignard thing in organic solvent.
2. the preparation method of methyl testosterone according to claim 1, is characterized in that, the concrete operations of three steps synthesis are as follows：
A, synthesis etherate：By 4AD in organic solvent with triethyl orthoformate under acid catalysiss, in 20～50 DEG C of stirring reactions
12～16 hours, add 0.02g weak base to be neutralized to pH 7～7.5, further work-up after having reacted, obtain etherate 3- ethoxy
Base-androstane -3,5 diene -17- ketone, its HPLC content 98.5～99.5%, weight yield 100～102%；
B, synthesis grignard thing：Magnesium powder, organic solvent are added to reactor stirring, temperature control, to 25-55 DEG C, is slowly added into first
Base alkyl halide, reacts 4-6 hour, until magnesium powder is wholly absent, obtains Grignard reagent standby；Again above-mentioned etherate is dissolved in organic
In solvent, stirring, temperature control to 40-60 DEG C, the slowly above-mentioned Grignard reagent got ready of Deca, about 1-1.5 hour drips off, then be incubated in
40～60 DEG C are reacted 2～3 hours, and TLC confirms reaction end, more slowly Deca acid, hydrolyze 2-3 hour, after having hydrolyzed, point water,
Washing, organic layer concentrating under reduced pressure reclaim organic solvent, then with ethanol, activated carbon decolorizing recrystallization, obtain grignard thing 3 ethyoxyl-
17a methyl-androst 3,5,-diene -17- alcohol, HPLC content more than 99.0%, weight yield 90～95%；
C, synthesizing methyl Testosterone：Above-mentioned grignard thing is dissolved in organic solvent, stirring, be incubated and slowly drip at 40～80 DEG C
Acid adding, reacts 10～12 hours, and TLC confirms reaction end, then with liquid adjusting PH with base to 6.8 ~ 7.2, reclaims organic solvent, temperature lowering water
Analysis, obtains methyl testosterone crude product；HPLC content 97.0-98.5%, weight yield 85.5-88.5%；Crude product dissolves in below C4 low-carbon (LC)
In alcohol, add activated carbon, be heated to reflux 1.5-2.0 hour, slightly cool down, filtered while hot, filter cake is with being equivalent to the grignard thing that feeds intake
Collection after the low-carbon alcohols washing of 0.5-1 part weight is processed, and washing liquid and filtrate merge, and normal pressure is concentrated into the solvent reclaiming 88-90%,
Then stop concentrating, be cooled to -5-0 DEG C, stirring and crystallizing 3-4 hour, filters, filtrate recycling design is applied mechanically with mother solution material, filter cake 100
Dry below DEG C, obtain methyl testosterone product, 162～167 DEG C of fusing point, HPLC content 99.0-99.5%, this step yield 80-82%.
3. the preparation method of methyl testosterone according to claim 1, is characterized in that, organic described in above-mentioned etherate synthesis
Solvent, including dichloromethane, toluene, methanol, ethanol；Reaction acid catalyst used includes hydrochloric acid, sulphuric acid, phosphoric acid, and acetic acid is right
Toluenesulfonic acid, oxalic acid；Weak base used by neutralization includes sodium carbonate or pyridine, 20～50 DEG C of reaction temperature；The weight proportion of reactant
It is, 4AD：Triethyl orthoformate：Acid=1：0.5～1.0:0.01～0.05；Proportioning between reactant and solvent is, 4AD：Organic
Solvent=1g：2～8ml；
Above-mentioned grignard thing synthesizes the organic solvent of described grignard reaction, including toluene, benzene, chloroform, oxolane, dioxane；
The organic solvent of Grignard reagent preparation includes ether, oxolane；The methyl halogenated alkane of reagent includes chloromethanes, bromomethane, iodine first
Alkane；Hydrolysis acid used includes acetic acid, p-methyl benzenesulfonic acid or hydrochloric acid, sulphuric acid；Grignard reagent preparation reaction temperature is 25～55 DEG C,
Grignard reaction is 40～60 DEG C with the reaction temperature of hydrolysis；Weight proportion between reactant is, etherate：Magnesium：Halo first
Alkane：Grignard reagent solvent=1：0.2～0.5:0.8～1.5：2～5, the proportioning between reactant and solvent is：Etherate：Reaction
Organic solvent=1g：4～8ml；
Organic solvent used by methyl testosterone is prepared in above-mentioned grignard thing hydrolysis, and including toluene, acetone, formic acid, acetic acid, below C4 is low
Carbon alcohol such as methanol, ethanol, isopropanol, the tert-butyl alcohol；Described acid includes hydrochloric acid, sulphuric acid or trifluoroacetic acid, p-methyl benzenesulfonic acid；Reaction temperature
40～80 DEG C of degree；Weight proportion between reactant is：Grignard thing：Acid=1：0.6～1.2, the proportioning between reactant and solvent is,
Grignard thing：Organic solvent=1g：4-6ml.
4. the preparation method of methyl testosterone according to claim 2, is characterized in that,
Described in etherate synthesis, organic solvent is ethanol, and reaction acid catalyst used is p-methyl benzenesulfonic acid, neutralization reaction temperature
20～30 DEG C of degree；The weight proportion of reactant is, 4AD：Triethyl orthoformate：Acid=1：0.8：0.02; 4AD：Organic solvent=
1g::6～8ml；
The organic solvent of grignard reaction is toluene, and the organic solvent of Grignard reagent preparation is oxolane, the methyl halogenated alkane of reagent
It is bromomethane；Hydrolysis acid used is hydrochloric acid, and Grignard reagent prepares 40～45 DEG C of reaction temperature, grignard reaction and hydrolysis
Reaction temperature is 50～55 DEG C；Weight proportion between reactant is, etherate：Magnesium：Halide：Grignard reagent solvent=1：
0.35：1.2:3.5, etherate：Reaction organic solvent=1g：5ml；
Organic solvent used by synthesizing methyl Testosterone is acetic acid or ethanol, and described acid is hydrochloric acid；60～65 DEG C of reaction temperature；Reaction
Weight proportion between thing is：Grignard thing：Acid=1：0.8；Grignard thing：Organic solvent=1g：5ml.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610800810.4A CN106397520A (en) | 2016-09-02 | 2016-09-02 | Preparation method of methyltestosterone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610800810.4A CN106397520A (en) | 2016-09-02 | 2016-09-02 | Preparation method of methyltestosterone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106397520A true CN106397520A (en) | 2017-02-15 |
Family
ID=57998688
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610800810.4A Pending CN106397520A (en) | 2016-09-02 | 2016-09-02 | Preparation method of methyltestosterone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106397520A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107312051A (en) * | 2017-07-24 | 2017-11-03 | 湖南科瑞生物制药股份有限公司 | The preparation method of Mestanlone |
| CN107501373A (en) * | 2017-08-29 | 2017-12-22 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of danabol |
| CN107513090A (en) * | 2017-10-25 | 2017-12-26 | 湖南科瑞生物制药股份有限公司 | The preparation method of megestrol acetate |
| CN107629101A (en) * | 2017-09-28 | 2018-01-26 | 湖南科瑞生物制药股份有限公司 | The preparation method of the carboxylic acid of 17 3 ketone of β androstane-14s alkene 17 |
| CN109456381A (en) * | 2018-12-18 | 2019-03-12 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of Delmadinone |
| CN109627273A (en) * | 2018-12-05 | 2019-04-16 | 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 furazabol intermediate androstane |
| CN110003297A (en) * | 2018-01-04 | 2019-07-12 | 上海安谱实验科技股份有限公司 | A kind of methyltestosterone and its synthetic method of stable isotope labeling |
| CN113845555A (en) * | 2021-09-30 | 2021-12-28 | 丽江映华生物药业有限公司 | Progesterone production method |
| CN115286672A (en) * | 2022-08-16 | 2022-11-04 | 黄冈人福药业有限责任公司 | Preparation method of nandrolone |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5549396A (en) * | 1978-10-03 | 1980-04-09 | Hokko Chem Ind Co Ltd | Preparation of 17alpha-methylsteroid |
| CN104262442A (en) * | 2014-10-10 | 2015-01-07 | 湖南科瑞生物科技有限公司 | Preparation method for progestin |
-
2016
- 2016-09-02 CN CN201610800810.4A patent/CN106397520A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5549396A (en) * | 1978-10-03 | 1980-04-09 | Hokko Chem Ind Co Ltd | Preparation of 17alpha-methylsteroid |
| CN104262442A (en) * | 2014-10-10 | 2015-01-07 | 湖南科瑞生物科技有限公司 | Preparation method for progestin |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107312051A (en) * | 2017-07-24 | 2017-11-03 | 湖南科瑞生物制药股份有限公司 | The preparation method of Mestanlone |
| CN107501373A (en) * | 2017-08-29 | 2017-12-22 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of danabol |
| CN107501373B (en) * | 2017-08-29 | 2019-11-05 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of danabol |
| CN107629101A (en) * | 2017-09-28 | 2018-01-26 | 湖南科瑞生物制药股份有限公司 | The preparation method of the carboxylic acid of 17 3 ketone of β androstane-14s alkene 17 |
| CN107629101B (en) * | 2017-09-28 | 2020-06-26 | 湖南科瑞生物制药股份有限公司 | Preparation method of 17 β -androst-4-ene-3-one-17-carboxylic acid |
| CN107513090A (en) * | 2017-10-25 | 2017-12-26 | 湖南科瑞生物制药股份有限公司 | The preparation method of megestrol acetate |
| CN107513090B (en) * | 2017-10-25 | 2019-11-05 | 湖南科瑞生物制药股份有限公司 | The preparation method of megestrol acetate |
| CN110003297A (en) * | 2018-01-04 | 2019-07-12 | 上海安谱实验科技股份有限公司 | A kind of methyltestosterone and its synthetic method of stable isotope labeling |
| CN109627273A (en) * | 2018-12-05 | 2019-04-16 | 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 furazabol intermediate androstane |
| CN109456381A (en) * | 2018-12-18 | 2019-03-12 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of Delmadinone |
| CN113845555A (en) * | 2021-09-30 | 2021-12-28 | 丽江映华生物药业有限公司 | Progesterone production method |
| CN115286672A (en) * | 2022-08-16 | 2022-11-04 | 黄冈人福药业有限责任公司 | Preparation method of nandrolone |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106397520A (en) | Preparation method of methyltestosterone | |
| CN104262442B (en) | The preparation method of Progesterone | |
| CN106496297A (en) | A kind of preparation method of stanolone | |
| CN105153258B (en) | The preparation method of 3-beta-hydroxy-androstane-17-ketone | |
| CN106518945A (en) | Preparation method of 6a-methyl hydrocortisone | |
| CN107629101B (en) | Preparation method of 17 β -androst-4-ene-3-one-17-carboxylic acid | |
| CN107312051A (en) | The preparation method of Mestanlone | |
| CN104327146A (en) | Novel method of synthesizing 17 alpha-hydroxyl progesterone | |
| CN107629102B (en) | Preparation method of nomegestrol acetate | |
| CN104119415B (en) | Method for preparing 17alpha-hydroxyprogesteron | |
| CN105801651B (en) | A kind of synthetic method of 17 α hydroxyl progesterones | |
| CN106518944B (en) | The preparation method of Methyllprednisolone | |
| CN107501373B (en) | A kind of preparation method of danabol | |
| CN105294798A (en) | Preparation method of 17beta-androst-4-ene-3-one-17-carboxylic acid | |
| CN103483172A (en) | Preparation for dibenzoyl methane | |
| CN106397521A (en) | Testosterone preparation method | |
| CN104725460A (en) | Preparation method of androst-4-ene-6beta,19-epoxy-3,17-dione | |
| CN106008660B (en) | The preparation method of deflazacort | |
| CN106083971B (en) | A kind of preparation method of the acid of 5 β cholane of (E) 3 α hydroxyls 6 ethylidene, 7 ketone 24 | |
| CN109369760B (en) | Method for preparing dehydromethyltestosterone | |
| CN109627275A (en) | A kind of bis- dehydrogenation -17a- hydroxyl progesterone product preparation methods of 1,6- | |
| CN107513090B (en) | The preparation method of megestrol acetate | |
| CN109456382A (en) | A method of preparing delmadinone acetate | |
| CN110483594A (en) | A method of synthesis azithromycin | |
| CN103694296B (en) | The preparation method of DHEA intermediate 3 β-acetoxy-androst-3,5-diene-17-ketone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170215 |
|
| WD01 | Invention patent application deemed withdrawn after publication |