CN105294798A - Preparation method of 17beta-androst-4-ene-3-one-17-carboxylic acid - Google Patents
Preparation method of 17beta-androst-4-ene-3-one-17-carboxylic acid Download PDFInfo
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Abstract
The invention discloses a preparation method of 17beta-androst-4-ene-3-one-17-carboxylic acid. The preparation method comprises the following specific operation steps of performing acid catalyzed reaction on 4AD (Androstenedione) and triethyl orthoformate in low-carbon alcohol organic solvent to obtain etherate 3-ethyoxyl-androst-3,5-diene-17-one; performing 17-situ addition on the obtained etherate and nitromethane in the organic solvent under the catalysis of ethanediamine to obtain a nitro compound; reducing the obtained nitro compound in the organic solvent with zinc powder, and hydrolyzing with acid to obtain 17beta-androst-4-ene-3-one-17-formaldehyde; oxidizing an intermediate obtained by hydrolyzing in the organic solvent with hydrogen peroxide to obtain a 17beta-androst-4-ene-3-one-17-formic acid crude product; recrystallizing the crude product through methyl alcohol to obtain a finished product. According to the preparation method, total yield of synthesis weight is 70 to 72 percent, and the content of HPLC (High Performance Liquid Chromatography) is 99.0 percent or over 99.0 percent. The method disclosed by the invention has the advantages of high production yield, low cost, good purity, stable quality, high recovery rate of solvent, economy and environment friendliness.
Description
Technical field
The invention belongs to the fabricating technology of steroid hormone pharmaceutical intermediate, be specifically related to the preparation method of a kind of prostatomegaly medicine Finasteride intermediate 17 β-androstane-4-alkene-3-one-17-carboxylic acid.
Background technology
Finasteride is a line clinical application for the treatment of elderly men prostatomegaly and hyperplasia of prostate at present, is also used for the treatment of early prostate cancer simultaneously.Due to the activity of 5α-reductase in Finasteride energy Selective depression human body, thus the testosterone blocked in body is converted into dihydrotestosterone, and make the atrophy because can not get Standone of the prostate gland of hyperplasia, therefore this medicine side effect is little, and determined curative effect, market potential is huge.The production of Finasteride is with intermediate 17 β-androstane-4-alkene-3-one-17-carboxylic acid for raw material, obtains through open loop, closed loop, hydrogenation, amidation, the reaction of dehydrogenation five step.
The conventional production methods of 17 β-androstane-4-alkene-3-one-17-carboxylic acid; extract diosgenin from Chinese yam plant; through protection; oxidation; cracking, eliminates, and obtaining key intermediate acetic acid gestation diene alcohol ketone (abbreviation diene) is raw material; obtain through shortening, bromoform reaction, hydrolysis, Ovshinsky oxidation four-step reaction, its synthetic route is shown in accompanying drawing 1.The wherein technique such as extraction, oxicracking, diolefin hydrogenation, bromoform reaction of diosgenin, produces waste water more, not easily processes, easy contaminate environment; The Ovshinsky oxidizing process adopted in production, need use steam distillation, and water consumption, energy consumption are large; Adopt active nickel or palladium carbon 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 rises day by day because of planting costs such as artificial, chemical fertilizer, cause saponin, the production cost of diene is doubled and redoubled, cause the production cost of 17 β-androstane-4-alkene-3-one-17-carboxylic acid and market value to increase substantially, already great effect was created to global Finasteride pharmaceutical market.
Summary of the invention
The object of the invention is to avoid above-mentioned traditional processing technology waste water many, energy consumption is high, not easily process, easy contaminate environment, many deficiencies such as have potential safety hazard, production cost high, a kind of preparation method of 17 β-androstane-4-alkene-3-one-17-carboxylic acid is newly provided, significantly reduce production cost, reduce water consumption, energy consumption, make production process safety and environmental protection.
Technical scheme of the present invention is: the preparation method of 17 β-androstane-4-alkene-3-one-17-carboxylic acid, with 4-AD (i.e. 4AD) for raw material, first synthesizes etherate, secondary synthesizing nitryl thing, again through reduction and acid hydrolysis, be oxidized to obtain 17 β-androstane-4-alkene-3-one-17-carboxylic acid, concrete operation step is:
1) synthesize etherate, 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;
2) synthesizing nitryl thing, by above-mentioned gained etherate in organic solvent with Nitromethane 99Min. under quadrol catalysis, 17 additions obtain nitro compounds 3-oxyethyl group-20-nitro-androstane-3,5,17(20)-triolefin;
3) reduction and acid hydrolysis, by above-mentioned gained nitro compounds in low-carbon alcohol organic solvent, with zinc powder reduction, then acid hydrolysis obtains 17 β-androstane-4-alkene-3-one-17-formaldehyde;
4) be oxidized, by 17 β-androstane-4-alkene-3-one-17-formaldehyde in organic solvent, obtain 17 β-androstane-4-alkene-3-one-17-carboxylic acid with hydrogen peroxide oxidation;
Above-mentioned organic solvent comprises: ethanol, Nitromethane 99Min., toluene, methyl alcohol, methylene dichloride, chloroform, Virahol, the trimethyl carbinol;
Above-mentioned acid catalyst comprises: hydrochloric acid, toluenesulphonic acids, quadrol, sulfuric acid, phosphoric acid, acetic acid, oxalic acid.
The first step, synthesis etherate, be 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 in 0.02g weak base to pH7 ~ 7.5, add 3ml pyridine, stir 20-25 minute neutralizing acid, cooling, stirred crystallization 2 ~ 3 hours, suction filtration, washing with alcohol, washing lotion and filtrate merge; Filter cake less than 70 DEG C oven dry, obtains etherate 3-oxyethyl group-androstane-3,5 diene-17-ketone, its HPLC content 98.5 ~ 99.5%, weight yield 100 ~ 102%;
Above-mentioned organic solvent comprises methylene dichloride, toluene, below C4 low-carbon alcohol as methyl alcohol, ethanol, preferred alcohol, safety and environmental protection, convenient recovery; Acid catalyst used comprises hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, tosic acid, oxalic acid, preferred tosic acid, and catalytic effect is good; Neutralizing weak base used is sodium carbonate or pyridine, temperature of reaction 20 ~ 50 DEG C, preferably 20 ~ 30 DEG C; The weight proportion of reactant is, 4AD: triethyl orthoformate: acid=1:0.5 ~ 1.0:0.01 ~ 0.05, preferred 1:0.8:0.02; Proportioning between reactant and solvent is: 4AD: organic solvent=1g::6 ~ 8ml, preferred 1g::6 ~ 8ml.
Second step, synthesizing nitryl thing, be dissolved in organic solvent by above-mentioned etherate, 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)-triolefin, HPLC content more than 99.0%, weight yield 100 ~ 105%;
Above-mentioned organic solvent, comprises toluene, benzene, chloroform, tetrahydrofuran (THF), dioxane, Nitromethane 99Min., preferred Nitromethane 99Min.; Alkaline catalysts comprises the quadrol of quadrol and various N-replacement, preferred quadrol; Temperature of reaction is 80 ~ 90 DEG C; Weight proportion between reactant is: etherate: Nitromethane 99Min.: alkali=1:0.5 ~ 0.8:0.05 ~ 0.15, preferred 1:0.6:0.1; Proportioning between reactant and solvent is: etherate: organic solvent=1g:4 ~ 8ml, preferably 1g:6ml.
3rd step, reduction and hydrolysis, dissolve in organic solvent by above-mentioned itrated compound, add zinc powder, stirs, be incubated and slowly drip acid at 60 ~ 80 DEG C, react 3 ~ 6 hours, after having reacted, reclaim organic solvent, cooling elutriation, obtains 17 β-androstane-4-alkene-3-one-17-formaldehyde.HPLC content 96.0-98.5, weight yield 75.5-78.5%;
Above-mentioned organic solvent, comprises below C4 unary fatty acid (formic acid, acetic acid), below C4 low-carbon alcohol (methyl alcohol, ethanol, Virahol, the trimethyl carbinol), preferred acetic acid or ethanol; Described acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, preferred hydrochloric acid; Temperature of reaction 60 ~ 80 DEG C, preferably 60 ~ 65 DEG C; Weight proportion between reactant is, nitro compounds: zinc: acid=1:0.5 ~ 1.0:0.6 ~ 1.2, preferred 1:0.6:0.8; Proportioning between reactant and solvent is, nitro compounds: organic solvent=1g:4 ~ 6ml, preferably 1g:5ml.
4th step, oxidizing reaction, by above-mentioned 17 β-androstane-4-alkene-3-one-17-formaldehyde dissolves in organic solvent, add hydrogen peroxide and a small amount of acid catalyst, stir, be incubated and react 3 ~ 6 hours at 10 ~ 40 DEG C, after having reacted, reclaim organic solvent, cooling elutriation, obtains 17 β-androstane-4-alkene-3-one-17-formic acid crude product, crude product, through below C4 low-carbon alcohol recrystallization, obtains 17 β-androstane-4-alkene-3-one-17-formic acid.Fusing point 244-246 DEG C, HPLC content more than 99.0%, this step weight yield 90-92%, four step weight total recovery 70-72%;
Above-mentioned organic solvent, comprises toluene, chloroform, dioxane, tetrahydrofuran (THF), methyl-sulphoxide, ethyl acetate, below C4 low-carbon alcohol (methyl alcohol, ethanol, Virahol, the trimethyl carbinol); Preferred toluene, methyl alcohol, ethyl acetate; Described acid catalyst comprises hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, preferred hydrochloric acid; Temperature of reaction 10 ~ 40 DEG C, preferably 25 ~ 30 DEG C; Weight proportion between reactant is: formaldehyde thing: hydrogen peroxide: acid=1:0.2 ~ 0.5:0.005 ~ 0.01, preferred 1:0.35:0.008; Proportioning between reactant and solvent is, formaldehyde thing: organic solvent=1g:4 ~ 6ml, preferred 1g:5ml;
Crude product recrystallization solvent for use is below C4 low-carbon alcohol, particular methanol, both economical, effective again.The material proportion of recrystallization is, crude product: solvent=1:4 ~ 8, preferably 1:5.
the invention has the beneficial effects as follows: be that 17 β-androstane-4-alkene-3-one-17-carboxylic acid prepared by raw material with 4AD, relatively make the traditional method of raw material with diosgenin, raw material sources are extensive, process economics environmental protection, and reduce water consumption, energy consumption, production cost declines to a great extent.The inventive method is compared with conventional production methods, and processing condition are gentle, and technological operation is easy, and product yield is high, and quality is good.Calculate with the current prices of raw and semifnished materials, raw materials cost reduces 30-40%; 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 the process route chart of traditional mode of production 17 β-androstane-4-alkene-3-one-17-formic acid;
Fig. 2 is the process route chart that the present invention produces 17 β-androstane-4-alkene-3-one-17-formic acid.
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 Nitromethane 99Min., 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, 17 β-androstane-4-alkene-3-one-17-formaldehyde
In a 1000ml there-necked flask, add 100g nitro compounds, 500ml ethanol, 60g zinc powder is added under stirring at normal temperature, slowly be warming up to 60 ~ 65 DEG C, drip 30% hydrochloric acid soln 240ml, within about 1.5 ~ 2 hours, drip off, after dripping off, insulation reaction 4 ~ 5 hours, after having reacted, underpressure distillation, reclaim the ethanol of about 90 ~ 95%, then add 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, obtain 17 β-androstane-4-alkene-3-one-17-formaldehyde 78.5g.HPLC content 97.5%, yield 78.5%.
The preparation of D, 17 β-androstane-4-alkene-3-one-17-formic acid
In a 1000ml there-necked flask, add the above-mentioned formaldehyde thing of 100g, 500ml methyl alcohol, under stirring at normal temperature, add 35g hydrogen peroxide, 0.8g hydrochloric acid, insulation reaction 4 ~ 5 hours, after having reacted, underpressure distillation, reclaims the methyl alcohol 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 17 β-androstane-4-alkene-3-one-17-formic acid crude product.Above-mentioned crude product is dissolved in 600ml methyl alcohol, temperature rising reflux 2-3 hour, the methyl alcohol of normal pressure concentration and recovery about 70%, is then cooled to-5 ~ 0 DEG C, freezing crystallization 2 ~ 3 hours, filter, a small amount of methanol wash of filter cake, less than 70 DEG C oven dry, obtain 17 β-androstane-4-alkene-3-one-17-formic acid 91.5g, fusing point 244.5 ~ 245.5 DEG C, HPLC content 99.5%, yield 91.5%.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, 17 β-androstane-4-alkene-3-one-17-formaldehyde
In a 1000ml there-necked flask, add 100g nitro compounds, 500ml Glacial acetic acid, 60g zinc powder is added under stirring at normal temperature, slowly be warming up to 60 ~ 65 DEG C, drip the hydrochloric acid soln 240ml of 30%, within about 1.5 ~ 2 hours, drip off, after dripping off, insulation reaction 4 ~ 5 hours, after having reacted, underpressure distillation, reclaim the Glacial acetic acid of about 90-95%, then add 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, obtain 17 β-androstane-4-alkene-3-one-17-formaldehyde 77.5g.HPLC content 97.0%, yield 77.5%.
The preparation of D, 17 β-androstane-4-alkene-3-one-17-formic acid
In a 1000ml there-necked flask, add the above-mentioned formaldehyde thing of 100g, 500ml toluene, under stirring at normal temperature, add 35g hydrogen peroxide, 0.8g hydrochloric acid, insulation reaction 4 ~ 5 hours, after having reacted, underpressure distillation, reclaims the toluene 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 17 β-androstane-4-alkene-3-one-17-formic acid crude product.Above-mentioned crude product is dissolved in 600ml methyl alcohol, temperature rising reflux 2-3 hour, the methyl alcohol of normal pressure concentration and recovery about 70%, is then cooled to-5 ~ 0 DEG C, freezing crystallization 2 ~ 3 hours, filter, a small amount of methanol wash of filter cake, less than 70 DEG C oven dry, obtain 17 β-androstane-4-alkene-3-one-17-formic acid 90.0g, fusing point 244.0 ~ 245.5 DEG C, HPLC content 99.0%, yield 90.0%.Disposing mother liquor solvent and crude product are applied mechanically.
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, 17 β-androstane-4--alkene-3 ketone-17-formaldehyde
In a 1000ml there-necked flask, add 100g nitro compounds, 500ml ethanol, 60g zinc powder is added under stirring at normal temperature, slowly be warming up to 60 ~ 65 DEG C, drip the sulphuric acid soln 240ml of 50%, within about 1.5 ~ 2 hours, drip off, after dripping off, insulation reaction 4 ~ 5 hours, after having reacted, underpressure distillation, reclaim the ethanol of about 90-95%, then add 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, obtain 17 β-androstane-4-alkene-3-one-17-formaldehyde 78.0g.HPLC content 97.0%, yield 78.0%.
The preparation of D, 17 androstane-4-alkene β-3-ketone-17-formic acid
In a 1000ml there-necked flask, add the above-mentioned formaldehyde thing of 100g, 500ml ethyl acetate, under stirring at normal temperature, add 35g hydrogen peroxide, 0.8g hydrochloric acid, insulation reaction 4 ~ 5 hours, after having reacted, underpressure distillation, reclaims the ethyl acetate 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 17 β-androstane-4-alkene-3-one-17-formic acid crude product.Above-mentioned crude product is dissolved in 600ml methyl alcohol, temperature rising reflux 2-3 hour, the methyl alcohol of normal pressure concentration and recovery about 70%, is then cooled to-5 ~ 0 DEG C, freezing crystallization 2 ~ 3 hours, filter, a small amount of methanol wash of filter cake, less than 70 DEG C oven dry, obtain 17 β-androstane-4-alkene-3-one-17-formic acid 91.5g, fusing point 244.5 ~ 245.5 DEG C, HPLC content 99.2%, yield 91.5%.Disposing mother liquor solvent and crude product are applied mechanically.
Claims (6)
- The preparation method of 1.17 β-androstane-4-alkene-3-one-17-carboxylic acid, is characterized in that: be raw material with 4-AD, first synthesizes etherate, secondary synthesizing nitryl thing, again through reduction and acid hydrolysis, be oxidized to obtain 17 β-androstane-4-alkene-3-one-17-carboxylic acid, concrete operation step is:1) synthesize etherate, 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;2) synthesizing nitryl thing, by above-mentioned gained etherate in organic solvent with Nitromethane 99Min. under quadrol catalysis, 17 additions obtain nitro compounds 3-oxyethyl group-20-nitro-androstane-3,5,17(20)-triolefin;3) reduction and acid hydrolysis, by above-mentioned gained nitro compounds in low-carbon alcohol organic solvent, with zinc powder reduction, then acid hydrolysis obtains 17 β-androstane-4-alkene-3-one-17-formaldehyde;4) oxidizing reaction, by 17 β-androstane-4-alkene-3-one-17-formaldehyde in organic solvent, obtains 17 β-androstane-4-alkene-3-one-17-carboxylic acid with hydrogen peroxide oxidation;Above-mentioned organic solvent is selected from: ethanol, Nitromethane 99Min., toluene, methyl alcohol, methylene dichloride, chloroform, Virahol, the trimethyl carbinol;Above-mentioned acid catalyst is selected from: hydrochloric acid, toluenesulphonic acids, quadrol, sulfuric acid, phosphoric acid, acetic acid, oxalic acid.
- 2. the preparation method of 17 β according to claim 1-androstane-4-alkene-3-one-17-carboxylic acid, it is characterized in that, synthesis etherate be 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%;Organic solvent selects ethanol; Toluenesulphonic acids selected by acid catalyst; Neutralizing weak base used is sodium carbonate or pyridine, temperature of reaction 20 ~ 30 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::6 ~ 8ml.
- 3. the preparation method of 17 β according to claim 1-androstane-4-alkene-3-one-17-carboxylic acid, it is characterized in that, synthesizing nitryl thing is dissolved in organic solvent by above-mentioned etherate, 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)-triolefin, HPLC content more than 99.0%, weight yield 100 ~ 105%;Above-mentioned organic solvent, is selected from Nitromethane 99Min., toluene, benzene, chloroform, tetrahydrofuran (THF), dioxane; Alkaline catalysts comprises quadrol; Temperature of reaction is 80 ~ 90 DEG C; Weight proportion between reactant is: etherate: Nitromethane 99Min.: quadrol=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 17 β according to claim 1-androstane-4-alkene-3-one-17-carboxylic acid, it is characterized in that, reduction and acid hydrolysis are dissolved 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 17 β-androstane-4-alkene-3-one-17-formaldehyde; HPLC content 96.0-98.5, weight yield 75.5-78.5%;Above-mentioned organic solvent selects acetic acid or ethanol, and hydrochloric acid is selected in acid, temperature of reaction 60 ~ 80 DEG C; Weight proportion between reactant is, nitro compounds: zinc: acid=1:0.5 ~ 1.0:0.6 ~ 1.2, preferred 1:0.6:0.8; Proportioning between reactant and solvent is, nitro compounds: organic solvent=1g:4 ~ 6ml.
- 5. the preparation method of 17 β according to claim 1-androstane-4-alkene-3-one-17-carboxylic acid, it is characterized in that, oxidation is by above-mentioned 17 β-androstane-4-alkene-3-one-17-formaldehyde dissolves in organic solvent, add hydrogen peroxide and acid catalyst, stir, be incubated and react 3 ~ 6 hours at 10 ~ 40 DEG C, after having reacted, reclaim organic solvent, cooling elutriation, obtains 17 β-androstane-4-alkene-3-one-17-formic acid crude product; Crude product, through below C4 low-carbon alcohol recrystallization, obtains 17 β-androstane-4-alkene-3-one-17-formic acid; Fusing point 244-246 DEG C, HPLC content more than 99.0%, this step weight yield 90-92%, four step weight total recovery 70-72%;Above-mentioned organic solvent is selected from toluene or methyl alcohol, and hydrochloric acid selected by acid catalyst, temperature of reaction 25 ~ 30 DEG C; Weight proportion between reactant is, formaldehyde thing: hydrogen peroxide: acid=1:0.2 ~ 0.5:0.005 ~ 0.01, preferred 1:0.35:0.008; Proportioning between reactant and solvent is, formaldehyde thing: organic solvent=1g:4 ~ 6ml;Crude product recrystallization solvent for use is methyl alcohol, and the material proportion of recrystallization is, crude product: solvent=1:4 ~ 8.
- 6. the preparation method of the 17 β-androstane-4-alkene-3-one-17-carboxylic acid according to claim 1 or 2 or 3 or 4 or 5, is characterized in that,The first step synthesis etherate, the weight proportion of reactant is, 4AD: triethyl orthoformate: acid=1:0.8:0.02; Proportioning between reactant and solvent is, 4AD: organic solvent=1g::6 ~ 8ml;Second step synthesizing nitryl thing, the weight proportion between reactant is, etherate: Nitromethane 99Min.: alkali=1:0.6:0.1; Proportioning between reactant and solvent is, etherate: organic solvent=1g:6ml;3rd step reduction and acid hydrolysis, the weight proportion between reactant is, nitro compounds: zinc: acid=1:0.6:0.8; Proportioning between reactant and solvent is, nitro compounds: organic solvent=1g:5ml;4th step oxidizing reaction, the weight proportion between reactant is: formaldehyde thing: hydrogen peroxide: acid=1:0.35:0.008; Proportioning between reactant and solvent is, formaldehyde thing: organic solvent=1g:5ml.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732757A (en) * | 2016-03-02 | 2016-07-06 | 湖南科瑞生物制药股份有限公司 | Progesterone preparation method |
| CN109467584A (en) * | 2018-11-23 | 2019-03-15 | 湖南玉新药业有限公司 | - 17 β of androstane-4-alkene-3 -one-carboxylate methyl ester synthetic method |
| EP3875464A1 (en) * | 2020-03-06 | 2021-09-08 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Process for the purification of etiocholenic acid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262442A (en) * | 2014-10-10 | 2015-01-07 | 湖南科瑞生物科技有限公司 | Preparation method for progestin |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732757A (en) * | 2016-03-02 | 2016-07-06 | 湖南科瑞生物制药股份有限公司 | Progesterone preparation method |
| CN109467584A (en) * | 2018-11-23 | 2019-03-15 | 湖南玉新药业有限公司 | - 17 β of androstane-4-alkene-3 -one-carboxylate methyl ester synthetic method |
| CN109467584B (en) * | 2018-11-23 | 2021-05-11 | 湖南玉新药业有限公司 | Synthesis method of androstane-4-alkene-3-ketone-17 beta-methyl carboxylate |
| EP3875464A1 (en) * | 2020-03-06 | 2021-09-08 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Process for the purification of etiocholenic acid |
| CN113429449A (en) * | 2020-03-06 | 2021-09-24 | F.I.S.-菲博利佳意大利合成面料股份公司 | Method for purifying cholenic acid |
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