CN104262442B - The preparation method of Progesterone - Google Patents

The preparation method of Progesterone Download PDF

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Publication number
CN104262442B
CN104262442B CN201410531089.4A CN201410531089A CN104262442B CN 104262442 B CN104262442 B CN 104262442B CN 201410531089 A CN201410531089 A CN 201410531089A CN 104262442 B CN104262442 B CN 104262442B
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progesterone
acid
organic solvent
etherate
alcohol
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CN104262442A (en
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胡爱国
谢来宾
吴来喜
谢勇
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Hunan Kerey Pharmaceutical Co Ltd
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Hunan Kerey Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

The preparation method of Progesterone, take 4-AD as raw material, its operational path is, A, synthesis etherate, first by 4-AD and triethyl orthoformate in the organic solvent such as methylene dichloride, low-carbon alcohol, acid catalyzed reaction obtains etherate 3-oxyethyl group-androstane-3,5-diene-17-ketone; B, synthesizing nitryl thing, be by etherate in organic solvent with nitroethane under quadrol catalysis, 17 additions obtain nitro compounds 3-oxyethyl group-20-nitro-pregnant steroid-3,5,17(20)-triolefin; C, synthesis Progesterone, be by nitro compounds in the organic solvent such as acetic acid, low-carbon alcohol, with zinc powder reduction, acid hydrolysis obtains Progesterone crude product again, Progesterone crude product alcohol, decolorizing with activated carbon refine to obtain Progesterone, HPLC content more than 99.5%, fusing point 128 ~ 131 DEG C, synthesis weight total recovery 83 ~ 87%.The inventive method produces Progesterone, and yield is high, and purity is good, steady quality, and solvent recovering rate is high, economic environmental protection.

Description

The preparation method of Progesterone
Technical field
The invention belongs to the fabricating technology of steroid hormone medicine, be specifically related to a kind of preparation method of progestational hormone medicine Progesterone.
Background technology
Progesterone is the endogenous progestogen of a kind of human body, plays an important role in human fertility's process.Be widely used in dysfunctional uterine hemorrhage clinically, threatened abortion and habitual abortion, menorrhagia, dysmenorrhoea, amenorrhoea, and endometriosis and advanced breast cancer, simultaneously also for birth control, be a kind of most basic progestational hormone medicine.
The conventional production methods of Progesterone; extract diosgenin from Chinese yam plant; through protection, oxicracking, elimination; key intermediate acetic acid gestation diene alcohol ketone (abbreviation diene) obtained is raw material; obtain through shortening, hydrolysis, Ovshinsky oxidation three-step reaction, its synthetic route is shown in accompanying drawing 1.Application number is the production method of the Progesterone that CN201210432390.0 and CN201110007899.1 announces is all above-mentioned traditional methods.The techniques such as the epoxidation of the wherein extraction of diosgenin, oxicracking, diene, produce waste water more, and not easily process, easy contaminate environment; The Ovshinsky oxidizing process that Progesterone is produced, adopts steam distillation, and water consumption, energy consumption are large; Adopt active nickel or palladium charcoal shortening, there is potential safety hazard.The more important thing is, along with wild Chinese yam plant resources is day by day exhausted, and artificial growth Chinese yam plant, also because of the rising day by day of the planting costs such as artificial, chemical fertilizer, cause saponin, the production cost of diene is doubled and redoubled, cause Progesterone production cost and market value to increase substantially, already great effect was created to global progestin drugs market; Number of patent application CN201210468281.4 discloses one with 17a-hydroxyl progesterone for raw material, and through acid catalysis deshydroxy, the novel process of active nickel or palladium charcoal shortening two step synthesis Progesterone, though processing method is simple and convenient, production cost is higher.Therefore find new wide material sources, diosgenin alternate resources cheap and easy to get, low cost production Progesterone bulk drug, is significant.Once there is bibliographical information abroad, and utilized the residue produced from soybean oil and extract Stigmasterol, through modern biotechnology fermentation technique, another key intermediate 4-AD of synthesizing steroid hormonal medicaments can be obtained, be called for short 4AD.4AD production technology is quite ripe at present, realizes large-scale industrial production, can produce most of steroid hormone medicine by 4AD in China.Obviously, the method has that raw material sources are extensive, and cheap and easy to get, key intermediate production operation is easy, and yield is higher, relative environmental protection, and total cost such as to decline to a great extent at the advantage, is the most Perfected process that alternative diosgenin resource produces steroid hormone medicine.The Chinese patent of application number CN201310615259.2 discloses a kind of with 1; 4-AD is the method (note: original text is wrong that Progesterone prepared by raw material; 1; 4-AD should be 4AD); be that raw material is through 3 etherification protections with 4AD; 17 cautious uncommon reactions Wei, the processing method of acidic hydrolysis three-step reaction synthesis Progesterone, its synthetic route is shown in accompanying drawing 2.Its concrete operations technique is as follows: add in reaction flask by 4AD, dehydrated alcohol, triethyl orthoformate, tosic acid, 40 DEG C of insulation reaction 3 hours, is neutralized to pH7.0 with pyridine, be cooled to 0 DEG C, filter, a small amount of ethanol is washed, obtain intermediate 3-oxyethyl group-androstane-3,5-diene-17-ketone; Again the tetrahydrofuran solution of (1-methoxyethyl)-triphenylphosphine a tetrafluoro borate is cooled to-50 DEG C, then potassium tert.-butoxide is added, insulation reaction is after 2 hours, add above-mentioned intermediate 3-oxyethyl group-androstane-3, the tetrahydrofuran solution of 5-diene-17-ketone, is slowly warming up to room temperature after adding, and adjusts pH to 1 with hydrochloric acid, concentrating under reduced pressure partial solvent, system is chilled to 0 DEG C of crystallization, filters, wash again after alkali cleaning, obtain Progesterone crude product, crude product ethyl alcohol recrystallization, obtains Progesterone, purity 96.5%, in 4AD, weight total recovery 75%.Obviously, this patent application is Material synthesis Progesterone with 4AD, and synthetic route is short, simple to operate, and yield is higher, and relative conventional production methods, cost significantly reduces.But gained impurity is many, of poor quality, purification difficult.If repeatedly refine, until up-to-standard, weight total recovery then only has 60-65%, and cost advantage is not obvious.
Summary of the invention
The object of this invention is to provide a kind of preparation method of new Progesterone, solve the defect that existing Progesterone production technology exists, reduce the production cost of Progesterone.
Technical scheme of the present invention is: the preparation method of Progesterone, for raw material, first synthesizes etherate, secondary synthesizing nitryl thing, resynthesis Progesterone with 4-AD (being called for short 4AD);
A synthesizes etherate, is that acid catalyzed reaction obtains etherate 3-oxyethyl group-androstane-3,5-diene-17-ketone by 4AD and triethyl orthoformate in low-carbon alcohol organic solvent;
B synthesizing nitryl thing, be by etherate in organic solvent with Nitromethane 99Min. under quadrol catalysis, 17 additions obtain nitro compounds 3-oxyethyl group-20-nitro-pregnant steroid-3,5,17 (20)-triolefin;
C synthesizes Progesterone, is by nitro compounds in low-carbon alcohol organic solvent, with zinc powder reduction, acid hydrolysis obtains Progesterone crude product again, and Progesterone crude product alcohol, decolorizing with activated carbon refine to obtain Progesterone, HPLC content more than 99.5%, fusing point 128 ~ 131 DEG C, synthesis weight total recovery 83 ~ 87%.
Wherein: the building-up reactions formula of A etherate is as follows:
By 4AD in organic solvent with triethyl orthoformate under acid catalysis, in 20 ~ 50 DEG C of stirring reactions 12 ~ 16 hours, after having reacted, add 0.02g weak base and be neutralized to pH7 ~ 7.5, further aftertreatment, obtains etherate 3-oxyethyl group-androstane-3,5 diene-17-ketone, its HPLC content 98.5 ~ 99.5%, weight yield 100 ~ 102%;
The above organic solvent, comprises methylene dichloride, toluene, below C4 low-carbon alcohol as methyl alcohol, ethanol, preferably ethanol, safety and environmental protection, convenient recovery; React acid catalyst used and comprise mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, or organic acid is as acetic acid, tosic acid, oxalic acid, preferably tosic acid, catalytic effect is good; Neutralize weak base used and comprise inorganic weak bases as sodium carbonate, or organic weak base is as pyridine, temperature of reaction 20 ~ 50 DEG C, 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, is 1g::6 ~ 8ml.
Wherein: the building-up reactions formula of B nitro compounds is as follows:
Above-mentioned etherate is dissolved in organic solvent, add Nitromethane 99Min., under Diethylamiues base catalysis, be warming up to 60 ~ 100 DEG C of reactions 6 ~ 8 hours, after having reacted, reclaim organic solvent, then with alcohol, activated carbon decolorizing recrystallization, obtain nitro compounds 3 oxyethyl group-20-nitro-pregnant steroid 3,5,17 (20)-triolefins, HPLC content more than 99.0%, weight yield 100 ~ 105%.
Above-mentioned organic solvent, comprises toluene, benzene, chloroform, tetrahydrofuran (THF), dioxane, Nitromethane 99Min., preferably Nitromethane 99Min., both made solvent, do reaction reagent again, and reaction effect is good; Alkaline catalysts comprises the quadrol of quadrol and various N-replacement, preferably quadrol; Temperature of reaction is 60 ~ 100 DEG C, best 80 ~ 90 DEG C; Weight proportion between reactant is: etherate: Nitromethane 99Min.: alkali=1:0.5 ~ 0.8:0.05 ~ 0.15, preferably 1:0.6:0.1; Proportioning between reactant and solvent is: etherate: organic solvent=1 g: 4 ~ 8ml, preferably 1g:6ml.
Wherein: the building-up reactions formula of C Progesterone is as follows:
Dissolve in organic solvent by above-mentioned itrated compound, add zinc powder, stir, be incubated and slowly drip acid at 60 ~ 80 DEG C, react 3 ~ 6 hours, after having reacted, reclaim organic solvent, cooling elutriation, obtains Progesterone crude product.By above-mentioned Progesterone crude product with alcohol, activated carbon decolorizing recrystallization, obtain Progesterone, fusing point 129 ~ 131 DEG C, content > 99%, yield 80 ~ 85%.
Above-mentioned organic solvent, comprises below C4 unary fatty acid as formic acid, acetic acid, below C4 low-carbon alcohol as methyl alcohol, ethanol, Virahol, the trimethyl carbinol, preferably acetic acid or alcohol, reaction effect is good, convenient reclaims; Described acid comprises mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid etc., or organic acid is as acetic acid, trifluoroacetic acid, oxalic acid, preferably hydrochloric acid, inexpensive environmental protection; Temperature of reaction 60 ~ 80 DEG C, best 60 ~ 65 DEG C; Weight proportion between reactant is: nitro compounds: zinc: acid=1:0.5 ~ 1.0:0.6 ~ 1.2, preferably 1:0.6:0.8; Proportioning between reactant and solvent is, nitro compounds: organic solvent=1g:4-6ml, preferably 1g:5ml.
The invention has the beneficial effects as follows: be that Progesterone prepared by raw material with 4AD, relatively make the traditional method of raw material with diosgenin, raw material sources are extensive, and process economics environmental protection, production cost declines to a great extent.The inventive method is compared with method described in CN201310615259.2, and processing condition are gentle, and technological operation is easy, and side reaction is few, and pure DEG C of intermediate is high, and therefore product yield is high, and quality is good, and cost is low.The solvent used in technique, recyclable recycled, both economical, environmental protection again, is extremely beneficial to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is Progesterone conventional synthesis route map;
Fig. 2 is the Progesterone synthetic route chart that CN2013106152592 announces;
Fig. 3 is Progesterone synthetic route chart of the present invention.
Embodiment
In order to illustrate in greater detail main points of the present invention and spirit, be explained for three embodiments below:
Embodiment one:
The preparation of A, etherate
In a 1000ml there-necked flask, add 100g4AD, 200ml ethanol, 80ml triethyl orthoformate, 2g tosic acid, be incubated in 20 ~ 25 DEG C of stirring reactions 12 ~ 16 hours, TLC detection reaction terminal, after having reacted, add 3ml pyridine, stir 20-25 minute neutralizing acid, then system is cooled to-5-0 DEG C, stirred crystallization 2 ~ 3 hours, suction filtration, a small amount of washing with alcohol, washing lotion and filtrate merge, and recycling design and crude product are applied mechanically; Filter cake less than 70 DEG C oven dry, obtains etherate 101.6g, HPLC content 99.2%, weight yield 101.6%.
The preparation of B, nitro compounds
In a 1000ml there-necked flask, add 100g etherate, 400ml nitroethane, 5ml quadrol, be incubated in 85-90 DEG C of stirring reaction 6 ~ 8 hours, TLC detection reaction terminal, after having reacted, concentrating under reduced pressure, reclaims Nitromethane 99Min. and applies mechanically.800ml alcohol is added in above-mentioned residual night, heating makes it dissolve, add 5g gac, reflux decolour 1 ~ 1.5 hour, filtered while hot, filter cake about 80ml alcohol foam washing, merging filtrate and washing lotion, normal pressure is concentrated into recovery about 85% alcohol, then adds 500ml pure water, continues to steam the solvent of about 150ml containing ethanol 50-60%, again system is cooled to 5 ~ 10 DEG C, stirring and crystallizing 2 ~ 3 hours, filters, and the filter cake ethanolic soln of a small amount of 50% washs, less than 70 DEG C oven dry, obtain nitro compounds 104.6g, HPLC content 99.2%, weight total recovery 104.6%.
The preparation of C, Progesterone
In a 1000ml there-necked flask, add 100g nitro compounds, 500ml ethanol, under stirring at normal temperature, add 60g zinc powder, slowly be warming up to 60 ~ 65 DEG C, drip the hydrochloric acid soln of 240ml30%, within about 1.5 ~ 2 hours, drip off, after dripping off, insulation reaction 4 ~ 5 hours, after having reacted, underpressure distillation, reclaims the ethanol of about 90-95%, then adds 600ml tap water, be cooled to 10 ~ 15 DEG C, stirring and crystallizing 2-3 hour, filter, be washed to neutrality, filter cake less than 70 DEG C oven dry, obtains Progesterone crude product.Above-mentioned Progesterone crude product is dissolved in 600ml alcohol, adds 5g gac, temperature rising reflux decolouring 1-1.5 hour, filtered while hot, 100ml ethanol wash filter cake, washing lotion and filtrate merge, the alcohol of normal pressure concentration and recovery about 90%, is then cooled to-5-0 DEG C, freezing crystallization 2-3 hour, filter, a small amount of ethanol wash of filter cake, less than 70 DEG C oven dry, obtain Progesterone 84.2g, fusing point 129.5-130.5 DEG C, HPLC content 99.7%, yield 84.2%.Disposing mother liquor solvent and crude product are applied mechanically.
Embodiment two:
The preparation of A, etherate
In a 1000ml there-necked flask, add 100g4AD, 600ml methylene dichloride, 80ml triethyl orthoformate, 2g tosic acid, be incubated in 20 ~ 25 DEG C of stirring reactions 12 ~ 16 hours, TLC detection reaction terminal, after having reacted, add 3ml pyridine, stir 20 ~ 25 minutes neutralizing acids, concentrating under reduced pressure, reclaim methylene dichloride, cooling, adds 100ml ethanol, then system is cooled to-5 ~ 0 DEG C, stirred crystallization 2 ~ 3 hours, suction filtration, a small amount of washing with alcohol, washing lotion and filtrate merge, and recycling design and crude product are applied mechanically; Filter cake less than 70 DEG C oven dry, obtains etherate 100.2g, HPLC content 99.4%, weight yield 100.2%.
The preparation of B, nitro compounds
In a 1000ml there-necked flask, add 100g etherate, 60ml nitroethane, 600ml toluene, 5ml quadrol, be incubated in 85-90 DEG C of stirring reaction 6 ~ 8 hours, TLC detection reaction terminal, after having reacted, concentrating under reduced pressure, reclaims toluene and applies mechanically; 800ml alcohol is added in above-mentioned residual night, heating makes it dissolve, add 5g gac, reflux decolour 1 ~ 1.5 hour, filtered while hot, filter cake about 80ml alcohol foam washing, merging filtrate and washing lotion, normal pressure is concentrated into recovery about 85% alcohol, then adds 500ml pure water, continues to steam the solvent of about 150ml containing ethanol 50 ~ 60%, again system is cooled to 5 ~ 10 DEG C, stirring and crystallizing 2 ~ 3 hours, filters, and the filter cake ethanolic soln of a small amount of 50% washs, less than 70 DEG C oven dry, obtain nitro compounds 101.2g, HPLC content 99.0%, weight total recovery 101.2%:
The preparation of C, Progesterone
In a 1000ml there-necked flask, add 100g nitro compounds, 500ml Glacial acetic acid, under stirring at normal temperature, add 60g zinc powder, slowly be warming up to 60 ~ 65 DEG C, insulation reaction 4 ~ 5 hours, after having reacted, underpressure distillation, reclaims the acetic acid of about 90 ~ 95%, then adds 600ml tap water, be cooled to 10 ~ 15 DEG C, stirring and crystallizing 2 ~ 3 hours, filters, is washed to neutrality, filter cake less than 70 DEG C oven dry, obtains Progesterone crude product; Above-mentioned Progesterone crude product is dissolved in 600ml alcohol, adds 5g gac, temperature rising reflux decolouring 1 ~ 1.5 hour, filtered while hot, 100ml ethanol wash filter cake, washing lotion and filtrate merge, the alcohol of normal pressure concentration and recovery about 90%, is then cooled to-5 ~ 0 DEG C, freezing crystallization 2 ~ 3 hours, filter, a small amount of ethanol wash of filter cake, less than 70 DEG C oven dry, obtain Progesterone 81.4g, fusing point 129.5 ~ 130.5 DEG C, HPLC content 99.5%, yield 81.4%.
Embodiment three
The preparation of A, etherate
In a 1000ml there-necked flask, add 100g4AD, 200ml ethanol, 80ml triethyl orthoformate, pass into HCl gas 2g, airtight, be incubated in 2025 DEG C of stirring reactions 12 ~ 16 hours, TLC detection reaction terminal, after having reacted, add 3ml pyridine, stir 20 ~ 25 minutes neutralizing acids, then system is cooled to-5 ~ 0 DEG C, stirred crystallization 2 ~ 3 hours, suction filtration, a small amount of washing with alcohol, washing lotion and filtrate merge, and recycling design and crude product are applied mechanically; Filter cake less than 70 DEG C oven dry, obtains etherate 103.2g, HPLC content 99.1%, weight yield 103.2%.
The preparation of B, nitro compounds
In a 1000ml there-necked flask, add 100g etherate, 400ml nitroethane, 5mlN, N-Tetramethyl Ethylene Diamine, be incubated in 85 ~ 90 DEG C of stirring reactions 6 ~ 8 hours, TLC detection reaction terminal, after having reacted, concentrating under reduced pressure, reclaims Nitromethane 99Min. and applies mechanically.800ml alcohol is added in above-mentioned residual night, heating makes it dissolve, add 5g gac, reflux decolour 1 ~ 1.5 hour, filtered while hot, filter cake about 80ml alcohol foam washing, merging filtrate and washing lotion, normal pressure is concentrated into recovery about 85% alcohol, then adds 500ml pure water, continues to steam the solvent of about 150ml containing ethanol 50-60%, again system is cooled to 5 ~ 10 DEG C, stirring and crystallizing 2 ~ 3 hours, filters, and the filter cake ethanolic soln of a small amount of 50% washs, less than 70 DEG C oven dry, obtain nitro compounds 100.8g, HPLC content 99.2%, weight total recovery 100.8%.
The preparation of C, Progesterone
In a 1000ml there-necked flask, add 100g nitro compounds, 500ml ethanol, under stirring at normal temperature, add 60g zinc powder, slowly be warming up to 60 ~ 65 DEG C, drip the acid of 80ml trifluoroacetic acid, within about 1.5 ~ 2 hours, drip off, after dripping off, insulation reaction 4 ~ 5 hours, after having reacted, underpressure distillation, reclaims the ethanol of about 90-95%, then adds 600ml tap water, be cooled to 10 ~ 15 DEG C, stirring and crystallizing 2 ~ 3 hours, filter, be washed to neutrality, filter cake less than 70 DEG C oven dry, obtains Progesterone crude product.Above-mentioned Progesterone crude product is dissolved in 600ml alcohol, adds 5g gac, temperature rising reflux decolouring 1 ~ 1.5 hour, filtered while hot, 100ml ethanol wash filter cake, washing lotion and filtrate merge, the alcohol of normal pressure concentration and recovery about 90%, is then cooled to-5 ~ 0 DEG C, freezing crystallization 2 ~ 3 hours, filter, a small amount of ethanol wash of filter cake, less than 70 DEG C oven dry, obtain Progesterone 84.0g, fusing point 129.0 ~ 130.5 DEG C, HPLC content 99.5%, yield 84.0%.Disposing mother liquor solvent and crude product are applied mechanically.

Claims (4)

1. the preparation method of Progesterone, is characterized in that: be raw material with 4-AD, first synthesizes etherate, secondary synthesizing nitryl thing, resynthesis Progesterone;
A synthesizes etherate, first by 4-AD and triethyl orthoformate in low-carbon alcohol organic solvent, acid catalyzed reaction obtains etherate 3-oxyethyl group-androstane-3,5-diene-17-ketone;
B synthesizing nitryl thing, be by etherate in organic solvent with nitroethane under quadrol catalysis, 17 additions obtain nitro compounds 3-oxyethyl group-20-nitro-pregnant steroid-3,5,17 (20)-triolefin;
C synthesizes Progesterone, is by nitro compounds in low-carbon alcohol organic solvent, with zinc powder reduction, acid hydrolysis obtains Progesterone crude product again, and Progesterone crude product alcohol, activated carbon decolorizing refine to obtain Progesterone, HPLC content more than 99.5%, fusing point 128 ~ 131 DEG C, synthesis weight total recovery 83 ~ 87%.
2. the preparation method of Progesterone according to claim 1, it is characterized in that, the synthesis of etherate is, by 4AD in organic solvent with triethyl orthoformate under acid catalysis, in 20 ~ 50 DEG C of stirring reactions 12 ~ 16 hours, after having reacted, add 0.02g weak base and be neutralized to pH7 ~ 7.5, further aftertreatment, obtain etherate 3-oxyethyl group-androstane-3,5 diene-17-ketone, its HPLC content 98.5 ~ 99.5%, weight yield 100 ~ 102%;
Described organic solvent, is selected from methylene dichloride, toluene, methyl alcohol, ethanol; React acid catalyst used and be selected from hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid, tosic acid, oxalic acid; Neutralize weak base used and select sodium carbonate or pyridine, temperature of reaction 20 ~ 50 DEG C; The weight proportion of reactant 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.
3. the preparation method of Progesterone according to claim 1, is characterized in that, the synthesis of nitro compounds is, above-mentioned etherate is dissolved in organic solvent, adds nitroethane, under Diethylamiues base catalysis, be warming up to 60 ~ 100 DEG C of reactions 6 ~ 8 hours, after having reacted, reclaim organic solvent, then with alcohol, activated carbon decolorizing recrystallization, obtain 3-oxyethyl group-20-nitro-pregnant steroid 3,5,17 (20)-triolefin nitro compounds, HPLC content more than 99.0%, weight yield 100 ~ 105%;
Organic solvent described above, is selected from toluene, benzene, chloroform, tetrahydrofuran (THF), dioxane, nitroethane; Described alkaline catalysts is selected from the quadrol of quadrol and N-replacement; Temperature of reaction is 60 ~ 100 DEG C; Weight proportion between reactant is: etherate: nitroethane: alkali=1:0.5 ~ 0.8:0.05 ~ 0.15; Proportioning between reactant and solvent is, etherate: organic solvent=1g:4 ~ 8ml.
4. the preparation method of Progesterone according to claim 1, it is characterized in that itrated compound dissolves in organic solvent by the synthesis of Progesterone, add zinc powder, stir, be incubated and slowly drip acid at 60 ~ 80 DEG C, react 3 ~ 6 hours, after having reacted, reclaim organic solvent, cooling elutriation, obtains Progesterone crude product; By Progesterone crude product with alcohol, activated carbon decolorizing recrystallization, obtain Progesterone, fusing point 129 ~ 131 DEG C, content > 99%, yield 80 ~ 85%;
Organic solvent described above, is selected from formic acid, acetic acid, methyl alcohol, ethanol, Virahol, the trimethyl carbinol; Described acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, trifluoroacetic acid, oxalic acid; Reaction is 60 ~ 80 DEG C; Weight proportion between reactant is, nitro compounds: zinc: acid=1:0.5 ~ 1.0:0.6 ~ 1.2; Proportioning between reactant and solvent is: nitro compounds: organic solvent=1g:4 ~ 6ml.
CN201410531089.4A 2014-10-10 2014-10-10 The preparation method of Progesterone Active CN104262442B (en)

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CN105017363B (en) * 2015-06-25 2016-12-07 湖南科瑞生物制药股份有限公司 3-ketone-4-androstene-17 β carboxylic acid and the synthetic method of methyl ester thereof
CN105399790B (en) * 2015-10-28 2017-03-08 湖南科瑞生物制药股份有限公司 A kind of synthetic method of 3 ketone, 4 androstene 17 β carboxylic acid
CN105461776B (en) * 2015-10-28 2017-04-12 湖南科瑞生物制药股份有限公司 Synthetic method of progesterone
CN105294798A (en) * 2015-12-02 2016-02-03 湖南科瑞生物制药股份有限公司 Preparation method of 17beta-androst-4-ene-3-one-17-carboxylic acid
CN106397520A (en) * 2016-09-02 2017-02-15 湖南科瑞生物制药股份有限公司 Preparation method of methyltestosterone
CN106397521A (en) * 2016-09-02 2017-02-15 湖南科瑞生物制药股份有限公司 Testosterone preparation method
CN107417756A (en) * 2017-05-16 2017-12-01 浙江神洲药业有限公司 A kind of progesterone crystal formation and preparation method thereof
CN106928304A (en) * 2017-05-16 2017-07-07 浙江神洲药业有限公司 A kind of method for preparing progesterone
CN108084238A (en) * 2017-12-28 2018-05-29 广西万德药业有限公司 A kind of preparation method of canrenone intermediate

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