CN104292285A - Process for synthesizing high-content dehydronandrolon acetate - Google Patents
Process for synthesizing high-content dehydronandrolon acetate Download PDFInfo
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- UGYJARBOJBLRSI-UHFFFAOYSA-N CC(CC1)(C(CC2)C(CC3Br)C1C(CC1)C3=CC1=O)C2O Chemical compound CC(CC1)(C(CC2)C(CC3Br)C1C(CC1)C3=CC1=O)C2O UGYJARBOJBLRSI-UHFFFAOYSA-N 0.000 description 1
- ATHVCWWFRVEIAV-CPSFFCFKSA-N CC(CC1)(C(CC2)CC1C(CCC(OC(C)=O)=C1)/C1=C\C)C2=O Chemical compound CC(CC1)(C(CC2)CC1C(CCC(OC(C)=O)=C1)/C1=C\C)C2=O ATHVCWWFRVEIAV-CPSFFCFKSA-N 0.000 description 1
- AVILFMGAXJHBGL-TYUVMCHCSA-N CC(CC1)[C@]2(C)C1C1C=CC(CC(CC3)=[U])C3C1CC2 Chemical compound CC(CC1)[C@]2(C)C1C1C=CC(CC(CC3)=[U])C3C1CC2 AVILFMGAXJHBGL-TYUVMCHCSA-N 0.000 description 1
- HFLHHQWDPZNOPI-UHFFFAOYSA-N CC(CCC1C2CC3)(C(CC4)C1C=CC2=CC3=O)C4O Chemical compound CC(CCC1C2CC3)(C(CC4)C1C=CC2=CC3=O)C4O HFLHHQWDPZNOPI-UHFFFAOYSA-N 0.000 description 1
- OGUASZAAVFYYIL-UHFFFAOYSA-N CC(CCC1C2CC3)(C(CC4)C1C=CC2=CC3=O)C4OC(C)=O Chemical compound CC(CCC1C2CC3)(C(CC4)C1C=CC2=CC3=O)C4OC(C)=O OGUASZAAVFYYIL-UHFFFAOYSA-N 0.000 description 1
- ZXWFZDGQYIKWRW-UHFFFAOYSA-N CCCC(CCCC(CC1CC2)CC=C1C=C2OC(C)=O)=O Chemical compound CCCC(CCCC(CC1CC2)CC=C1C=C2OC(C)=O)=O ZXWFZDGQYIKWRW-UHFFFAOYSA-N 0.000 description 1
- LPIPZOILDHISHJ-BNXZHGPJSA-N C[C@](CC1)(C(CC2)C3C1C(CCC(OC(C)=O)=C1)C1=CC3)/C2=[O]\C(C)=O Chemical compound C[C@](CC1)(C(CC2)C3C1C(CCC(OC(C)=O)=C1)C1=CC3)/C2=[O]\C(C)=O LPIPZOILDHISHJ-BNXZHGPJSA-N 0.000 description 1
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- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
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Abstract
The invention provides a process for synthesizing high-content dehydronandrolon acetate. The process comprises the following five steps: 1, esterifying C-3 site of estr-4-ene-3,17-dione (1) serving as a starting raw material by using acetic anhydride under catalysis of toluenesulfonic acid to obtain a compound 2; 2, reducing carbonyl on the 17 site of the compound 2 into hydroxyl by using potassium borohydride at room temperature to obtain a compound 3; 3, reacting the compound 3 with NBS and DMF to obtain a compound 4; 4, reacting the compound 4 with lithium carbonate, lithium bromide and DMF to obtain a compound 5; 5, reacting the compound 5 with acetic anhydride and triethylamine to obtain the dehydronandrolon acetate. The synthesizing process is simple in condition, the industrial generation condition is easy to control, expensive reagent is not needed, consumption of reagent is reduced, production cost is reduced, and the 3-site carbonyl can be effectively controlled and protected; the process has short reaction route and low cost, is capable of improving yield and content, has a purity of over 99 percent (HPLC standard), and has remarkable comprehensive economic benefit. The process can be popularized and applied to all dehydronandrolon acetate production enterprises.
Description
Technical field
The present invention relates to the synthesis technique of dehydrogenation nandrolone acetic ester, especially one take female steroid-4-alkene-3,17-diketone as the synthesis technique of starting raw material synthesis of high content dehydrogenation nandrolone acetic ester.
Background technology
Dehydrogenation nandrolone acetic ester (dehydronandrolonacetate) is the key intermediate of synthesis fulvestrant (fulvestrant) and tibolone (tibolone) these two kinds of steroid drugss, fulvestrant is the new drug for the treatment of mammary cancer, tibolone is applied to the treatment of climacteric syndrome for a long time, its chemical name is 17b-Acetyloxy-estra-4,6-diene-3-one17 β acetic ester, female steroid-4,6-diene-3-ketone, English Dehydronandrolonacetate by name.
The synthesis technique of existing dehydrogenation nandrolone acetic ester has 3 kinds:
1; the synthesis technique of the dehydrogenation nandrolone acetic ester of patent WO2006015081 report is: take nandrolone as raw material; use acetic anhydride and Acetyl Chloride 98Min. to carry out acylation reaction simultaneously, then to use after NBS bromo cancellation molecule HBr under basic conditions, obtain dehydrogenation nandrolone acetic ester.This synthetic line cost is higher, and the double esterification reagent used has certain contaminative, and yield is not high yet.
Its operational path is:
2; the synthesis technique of the dehydrogenation nandrolone acetic ester that document " Chinese medicine company " 2006.15.p29 reports is: with female steroid-4-alkene-3; 17-diketone replaces expensive nandrolone to be raw material; under the catalysis of tosic acid, carry out selective protection 3 carbonyls with triethyl orthoformate obtain etherification product; after potassium borohydride reduction; under the effect of acetone and hydrochloric acid, slough protecting group again and obtain nandrolone; nandrolone again through NBS bromo through isopropenyl acetate double esterification, is finally sloughed HBr with highly basic again and is obtained dehydrogenation nandrolone acetic ester.Although the method reduces cost to a certain extent; improve yield; agents useful for same environmental friendliness; but experiment proves, in the first step etherification procedure, the efficiency of triethyl orthoformate selective protection 3 carbonyls is not high; and it is also uneconomical as etherifying reagent with triethyl orthoformate; in addition, the circuit of this synthesis technique is longer, and operation easier is high.
3; the synthesis technique of the dehydrogenation nandrolone acetic ester that " Chinese pharmaceutical chemistry " 2013.10.p368 reports is: with female steroid-4-alkene-3; 17-diketone (1) is starting raw material; with acetic anhydride, under the catalysis of tosic acid, directly carrying out esterification to C-3 position obtains compound 2; compound 2 at room temperature becomes hydroxyl to obtain compound 3 with sodium borohydride reduction 17 carbonyls; compound 3 obtains compound 4 by acetic anhydride acidylate under the catalysis of 4-dimethylaminopyridine (DMAP), and compound 4 is sloughed HBr again and obtained target compound 6 after NBS bromo under basic conditions.This operational path is:
This synthesis technique uses costly reagent D MAP, when sloughing HBr under basic conditions, is easily hydrolyzed acetic ester, obtains partial nandrolone, and product dehydrogenation nandrolone acetic ester purity is declined.
The applicant is through studying intensively, having invented and can effectively solve the expensive reagents used in existing synthesis technique; reaction times route is long; raw material consumption is large; effectively can not protect 3 carbonyls; the problem that yield and content are not high; the synthesis technique of high-content dehydrogenation nandrolone acetic ester that be more suitable for suitability for industrialized production feature, that take female steroid-4-alkene-3,17-diketone as starting raw material.
According to retrieval, domestic not yet have the patent application identical with the present invention.
Summary of the invention
The object of the invention is to: the invention provides a kind of synthetic technological condition simple, industrialization formation condition is easy to control, reaction scheme is short, with low cost, improve yield and content, purity reaches more than 99%, take female steroid-4-alkene-3,17-diketone as the synthesis technique of the high-content dehydrogenation nandrolone acetic ester of starting raw material.
Technical scheme of the present invention is: the synthesis technique of a kind of high-content dehydrogenation of the present invention nandrolone acetic ester is the synthesis technique of the high-content dehydrogenation nandrolone acetic ester taking female steroid-4-alkene-3,17-diketone as starting raw material, comprises following five steps:
The chemical structural formula of dehydrogenation nandrolone acetic ester of the present invention is as follows:
The synthesis route of a kind of high-content of the present invention dehydrogenation nandrolone acetic ester is as follows:
Described step (): directly carrying out esterification to C-3 position obtains compound 2 under the catalysis of tosic acid for starting raw material acetic anhydride with female steroid-4-alkene-3,17-diketone (1); The chemical equation of described operational path is:
Described step (two): compound 2 potassium borohydride reduction 17 carbonyls become hydroxyl to obtain compound 3; The chemical equation of described operational path is:
Described step (three): compound 3 and NBS and DMF react, and obtain compound 4; The chemical equation of described operational path is:
Described step (four): compound 4 and Quilonum Retard, lithiumbromide, DMF react, and obtain compound 5; The chemical equation of described operational path is:
Described step (five): compound 5 reacts with acetic anhydride and triethylamine, obtains compound 6---dehydrogenation nandrolone acetic ester; The chemical equation of described operational path is:
Concrete, the synthesis technique of described a kind of high-content dehydrogenation nandrolone acetic ester is in the following order, step, preparation method carry out:
Described step (): compound 2---Δ
3,5the preparation method of-female steroid-3-acetoxyl group-17-ketone (2):
With female steroid-4-alkene-3,17-diketone (1) makes it just dissolve for starting raw material adds acetic anhydride, add catalyzer tosic acid subsequently, after reacting about 15min in 15 DEG C, reaction solution occurs muddy, and adularescent solid is separated out, and adds saturated sodium bicarbonate solution and stir 1h after continuing reaction 2h, direct filtration when solid is Powdered being scattered in solution, wash solid with water 2 times, dry solid, obtain off-white powder shape compound 2---Δ
3,5-female steroid-3-acetoxyl group-17-ketone (2);
In described step (): female steroid-4-alkene-3,17-diketone (1) is 1g: 5ml with the ratio of the amount of acetic anhydride;
Described step (two): the preparation method of compound 3---female steroid-3,5-diene-17 β-ol-3-acetic ester (3):
Gained compound 2 is placed in reaction vessel, adds methyl alcohol, at 15 DEG C, add POTASSIUM BOROHYDRIDE, after 30min, reaction solution becomes clarification, drips Glacial acetic acid and adjusts pH value to be about 7.0, poured into by reaction solution in saturated aqueous common salt in solution, be extracted with ethyl acetate, merge organic phase, wash 2 times with clear water, to remove residual salt solution, anhydrous magnesium sulfate drying, decompression, is concentrated into and dryly obtains compound as white solid 3---female steroid-3,5-diene-17 β-ol-3-acetic ester (3);
In described step (two): compound 2 is 1g: 0.12g with the ratio of the amount of POTASSIUM BOROHYDRIDE;
Described step (three): the preparation method of compound 4:
Gained compound 3 is placed in reaction vessel, adds DMF and water, does not dissolve completely, another DMF dissolves NBS, is slowly added drop-wise in reaction soln by the DMF solution of NBS at-5 DEG C, dropwises in about 1h, at-5 DEG C of insulation 1h, compound 3 and NBS and DMF react, and obtain compound 4;
In described step (three): compound 3 is 1g: 0.5g: 30ml with the ratio of the amount of NBS and DMF;
Described step (four): compound 5---the preparation method of dehydrogenation nandrolone (5):
Gained compound 4 is removed cryosel bath, stirred at ambient temperature 30min, add sodium bisulfite, stir 10min, add lithiumbromide and Quilonum Retard subsequently, continue to stir 20min, 80 DEG C are slowly warming up in 1h, in 80 DEG C of reaction 2-3h, until bromination object point disappears, stop heating, gained light brown suspended substance is cooled to room temperature, drip acetum, add crystal seed a little, stirring is spent the night, separate solid, filter cake DMF-water, volume ratio is the mixed solution washing of 1:1, wash 2 times again with water, Virahol is added in crude product, be warming up to 45 DEG C, solution becomes brown, slow dropping water makes product precipitate---at least 30min, solution is cooled to 0-5 DEG C, stir 1h at this temperature, filter, filter cake 0-5 DEG C of isopropanol-water, volume ratio is the mixing solutions washing of 2:3, 50 DEG C of vacuum-dryings, obtain off-white color pressed powder compound 5---dehydrogenation nandrolone (5),
In described step (four): compound 4 is 1g: 0.6g: 0.3g: 2ml with the ratio of the amount of Quilonum Retard, lithiumbromide, DMF;
Described step (five): compound 6---the preparation method of dehydrogenation nandrolone acetic ester (6):
Gained compound 5, methylene dichloride, acetic anhydride, triethylamine are placed in reaction vessel, neutrality is washed till with saturated sodium bicarbonate solution after 45 DEG C of reaction 90min, till bubble not had produces, be separated organic layer, organic layer saturated common salt water washing, then wash 2 times with water, is evaporated to and dryly obtains off-white color solid crude product dehydrogenation nandrolone acetic ester (6), yield 93.4%, mp104-105 DEG C;
In described step (five): compound 5 is 1g: 12ml: 2.5ml: 0.015g with the ratio of the amount of methylene dichloride, acetic anhydride, triethylamine.
The invention has the beneficial effects as follows:
The reagent used in the synthesis technique of 1. existing preparation dehydrogenation nandrolone acetic ester is expensive, reagent consumption large, can not effective Control protection 3 carbonyls, synthetic technological condition of the present invention simply, does not need expensive reagent, reduces reagent consumption, reduction production cost, increase economic efficiency.
2. the synthesis technique circuit of existing preparation dehydrogenation nandrolone acetic ester is longer, and operation easier is high, and synthetic method craft circuit of the present invention shortens, and enhances productivity.
3. the synthesis technique yield of existing preparation dehydrogenation nandrolone acetic ester and content is not high, the demand that cannot meet suitability for industrialized production, use that synthesis technique yield of the present invention is high, content is high, more than 99% high-content dehydrogenation nandrolone acetic ester can be obtained, overall economic efficiency is remarkable, meets industrial production demand.
The present invention can be applied to all dehydrogenation nandrolone acetic ester manufacturing enterprises.
Embodiment
The invention will be further described to utilize embodiment.
Following examples, only in order to further illustrate the present invention, do not limit content of the present invention.
The present invention is with the synthesis technique of female steroid-4-alkene-3,17-diketone (1) for starting raw material synthesis of high content dehydrogenation nandrolone acetic ester.
Embodiment one
Step one: compound 2---Δ
3,5the preparation method of-female steroid-3-acetoxyl group-17-ketone (2):
Get 1.0g (3.67mmol) female steroid-4-alkene-3,17-diketone (1), adding 5.0ml acetic anhydride makes it just dissolve, add 0.05g (0.17mmol) tosic acid subsequently, after reacting about 15min in 15 DEG C, reaction solution occurs muddy, and adularescent solid is separated out, add 80ml saturated sodium bicarbonate solution after continuing reaction 2h and stir 1h, direct filtration when solid is Powdered being scattered in solution, wash solid with water 2 times, dry solid, obtain off-white powder shape solid Δ
3,5-female steroid-3-acetoxyl group-17-ketone (2) 1.12g, yield 97.2%, mp157-159 DEG C;
Step 2: the preparation method of compound 3---female steroid-3,5-diene-17 β-ol-3-acetic ester (3):
1.0g (3.18mmol) compound 2 is placed in reaction vessel, add 30ml methyl alcohol, fail to dissolve completely, 0.12g (0.32mmol) POTASSIUM BOROHYDRIDE is added at 15 DEG C, after 30min, reaction solution becomes clarification, in solution, drip Glacial acetic acid adjusts pH value to be about 7.0, reaction solution is poured in 100ml saturated aqueous common salt, extract by ethyl acetate (15ml × 3), merge organic phase, 2 times are washed with clear water, to remove residual salt solution, anhydrous magnesium sulfate drying, decompression, be concentrated into and dryly obtain compound as white solid 3---female steroid-3, 5-diene-17 β-ol-3-acetic ester (3) 0.95g, yield 94.9%, mp138-140 DEG C,
Step 3: the preparation method of compound 4:
0.8g (2.23mmol) compound 3 is placed in reaction vessel, add DMF14ml and water, do not dissolve completely, another DMF10ml dissolves NBS, at-5 DEG C, the DMF solution of 0.4gNBS is slowly added drop-wise in reaction soln, dropwises in about 1h, at-5 DEG C of insulation 1h, compound 3 and NBS and DMF react, and obtain compound 4;
Step 4: compound 5---the preparation method of dehydrogenation nandrolone (5):
The compound 4 obtained is removed cryosel bath, stirred at ambient temperature 30min, add 0.3g sodium bisulfite, stir 10min, add 0.3g lithiumbromide and 0.6g Quilonum Retard subsequently, continue to stir 20min, 80 DEG C are slowly warming up in 1h, in 80 DEG C of reaction 2-3h, until bromination object point disappears, stop heating, gained light brown suspended substance is cooled to room temperature, drip the mixing solutions of 0.9ml Glacial acetic acid and 5.6ml water, add crystal seed a little, stirring is spent the night, separate solid, filter cake 1.2mlDMF-water, volume ratio is the mixed solution washing of 1:1, wash 2 times again with water, 1.46ml Virahol is added in crude product, being warming up to 45 DEG C of solution becomes brown, slow dropping water makes product precipitate---at least 30min, solution is cooled to 0-5 DEG C, stir 1h at this temperature, filter, filter cake 4ml0-5 DEG C of isopropanol-water, volume ratio is the mixing solutions washing of 2:3, 50 DEG C of vacuum-dryings, obtain off-white color pressed powder compound 5---dehydrogenation nandrolone (5) 0.54g, yield 79%, mp160-170 DEG C,
Step 5: compound 6---the preparation method of dehydrogenation nandrolone acetic ester (6):
0.85g (2.68mmol) compound 5,10ml methylene dichloride, 2ml acetic anhydride, 0.01g (82 μm of ol) triethylamine are placed in reaction flask, neutrality is washed till with saturated sodium bicarbonate solution after 45 DEG C of reaction 90min, till bubble not had produces, be separated organic layer, organic layer saturated common salt water washing, wash 2 times again with water, be evaporated to and dryly obtain off-white color solid crude product compound 6---dehydrogenation nandrolone acetic ester (6) 0.9g, yield 93.4%, mp104-105 DEG C.
Embodiment two
Step one: compound 2---Δ
3,5the preparation method of-female steroid-3-acetoxyl group-17-ketone (2):
Get 1.0g (3.67mmol) female steroid-4-alkene-3,17-diketone (1), adding 9.0ml isopropenyl acetate makes it just dissolve, add 0.05g (0.17mmol) tosic acid subsequently, after dehydration reaction 15min, reaction solution occurs muddy, adds 80ml saturated sodium bicarbonate solution and stir 1h after continuing room temperature reaction 1h, direct filtration when solid is Powdered being scattered in solution, wash solid with water 2 times, dry solid, obtain off-white powder shape solid Δ
3,5-female steroid-3-acetoxyl group-17-ketone (2) 1.12g, yield 97.2%, mp157-159 DEG C;
Step 2: the preparation method of compound 3---female steroid-3,5-diene-17 β-ol-3-acetic ester (3):
1.0g (3.18mmol) compound 2 is placed in reaction vessel, add 30ml methyl alcohol (failing to dissolve completely), 0.12g (0.32mmol) sodium borohydride is added at 15 DEG C, after 30min, reaction solution becomes clarification, in solution, drip Glacial acetic acid adjusts pH value to be about 7.0, by reaction solution to entering in 100ml saturated aqueous common salt, extract by ethyl acetate (15ml × 3), merge organic phase, 2 times are washed with clear water, to remove residual salt solution, anhydrous magnesium sulfate drying, decompression, be concentrated into and dryly obtain compound as white solid 3---female steroid-3, 5-diene-17 β-ol-3-acetic ester (3) 0.95g, yield 94.9%, mp138-140 DEG C,
Step 3: the preparation method of compound 4 is identical with embodiment one step 3;
The preparation method of step 4: compound 5---dehydrogenation nandrolone (5) is identical with embodiment one step 4;
Step 5: compound 6---the preparation method of dehydrogenation nandrolone acetic ester (6):
0.85g (2.68mmol) compound 5,10ml methylene dichloride, 4ml acetic anhydride, 1ml pyridine are placed in reaction flask, neutrality is washed till with saturated sodium bicarbonate solution after 45 DEG C of reaction 60min, till bubble not had produces, be separated organic layer, organic layer saturated common salt water washing, then wash 2 times with water, is evaporated to and dryly obtains off-white color solid crude product compound 6---dehydrogenation nandrolone acetic ester (6) 0.9g, yield 93.4%, mp104-105 DEG C.
Claims (2)
1. the synthesis technique of a high-content dehydrogenation nandrolone acetic ester, it is characterized in that: the synthesis technique of this kind of high-content dehydrogenation nandrolone acetic ester is with female steroid-4-alkene-3,17-diketone is the synthesis technique of the high-content dehydrogenation nandrolone acetic ester of starting raw material, comprises following five steps:
The chemical structural formula of this dehydrogenation nandrolone acetic ester is as follows:
The synthesis route of this kind of high-content dehydrogenation nandrolone acetic ester is as follows:
The synthesis technique of this kind of high-content dehydrogenation nandrolone acetic ester comprises following five steps:
Described step (): directly carrying out esterification to C-3 position obtains compound 2 under the catalysis of tosic acid for starting raw material acetic anhydride with female steroid-4-alkene-3,17-diketone (1); The chemical equation of described operational path is:
Described step (two): compound 2 potassium borohydride reduction 17 carbonyls become hydroxyl to obtain compound 3; The chemical equation of described operational path is:
Described step (three): compound 3 and NBS and DMF react, and obtain compound 4; The chemical equation of described operational path is:
Described step (four): compound 4 and Quilonum Retard, lithiumbromide, DMF react, and obtain compound 5; The chemical equation of described operational path is:
Described step (five): compound 5 reacts with acetic anhydride and triethylamine, obtains compound 6---dehydrogenation nandrolone acetic ester; The chemical equation of described operational path is:
。
2. the synthesis technique of a kind of high-content dehydrogenation nandrolone acetic ester according to claim 1, is characterized in that: the synthesis technique of described a kind of high-content dehydrogenation nandrolone acetic ester is in the following order, step, preparation method carry out:
Described step (): compound 2---Δ
3,5the preparation method of-female steroid-3-acetoxyl group-17-ketone (2):
With female steroid-4-alkene-3,17-diketone (1) makes it just dissolve for starting raw material adds acetic anhydride, add catalyzer tosic acid subsequently, after reacting about 15min in 15 DEG C, reaction solution occurs muddy, and adularescent solid is separated out, and adds saturated sodium bicarbonate solution and stir 1h after continuing reaction 2h, direct filtration when solid is Powdered being scattered in solution, wash solid with water 2 times, dry solid, obtain off-white powder shape compound 2---Δ
3,5-female steroid-3-acetoxyl group-17-ketone (2);
In described step (): female steroid-4-alkene-3,17-diketone (1) is 1g: 5ml with the ratio of the amount of acetic anhydride;
Described step (two): the preparation method of compound 3---female steroid-3,5-diene-17 β-ol-3-acetic ester (3):
Gained compound 2 is placed in reaction vessel, adds methyl alcohol, at 15 DEG C, add POTASSIUM BOROHYDRIDE, after 30min, reaction solution becomes clarification, drips Glacial acetic acid and adjusts pH value to be about 7.0, poured into by reaction solution in saturated aqueous common salt in solution, be extracted with ethyl acetate, merge organic phase, wash 2 times with clear water, to remove residual salt solution, anhydrous magnesium sulfate drying, decompression, is concentrated into and dryly obtains compound as white solid 3---female steroid-3,5-diene-17 β-ol-3-acetic ester (3);
In described step (two): compound 2 is 1g: 0.12g with the ratio of the amount of POTASSIUM BOROHYDRIDE;
Described step (three): the preparation method of compound 4:
Gained compound 3 is placed in reaction vessel, adds DMF and water, does not dissolve completely, another DMF dissolves NBS, is slowly added drop-wise in reaction soln by the DMF solution of NBS at-5 DEG C, dropwises in about 1h, at-5 DEG C of insulation 1h, compound 3 and NBS and DMF react, and obtain compound 4;
In described step (three): compound 3 is 1g: 0.5g: 30ml with the ratio of the amount of NBS and DMF;
Described step (four): compound 5---the preparation method of dehydrogenation nandrolone (5):
Gained compound 4 is removed cryosel bath, stirred at ambient temperature 30min, add sodium bisulfite, stir 10min, add lithiumbromide and Quilonum Retard subsequently, continue to stir 20min, 80 DEG C are slowly warming up in 1h, in 80 DEG C of reaction 2-3h, until bromination object point disappears, stop heating, gained light brown suspended substance is cooled to room temperature, drip acetum, add crystal seed a little, stirring is spent the night, separate solid, filter cake DMF-water, volume ratio is the mixed solution washing of 1:1, wash 2 times again with water, Virahol is added in crude product, be warming up to 45 DEG C, solution becomes brown, slow dropping water makes product precipitate---at least 30min, solution is cooled to 0-5 DEG C, stir 1h at this temperature, filter, filter cake 0-5 DEG C of isopropanol-water, volume ratio is the mixing solutions washing of 2:3, 50 DEG C of vacuum-dryings, obtain off-white color pressed powder compound 5---dehydrogenation nandrolone (5),
In described step (four): compound 4 is 1g: 0.6g: 0.3g: 2ml with the ratio of the amount of Quilonum Retard, lithiumbromide, DMF;
Described step (five): compound 6---the preparation method of dehydrogenation nandrolone acetic ester (6):
Gained compound 5, methylene dichloride, acetic anhydride, triethylamine are placed in reaction vessel, neutrality is washed till with saturated sodium bicarbonate solution after 45 DEG C of reaction 90min, till bubble not had produces, be separated organic layer, organic layer saturated common salt water washing, then wash 2 times with water, is evaporated to and dryly obtains off-white color solid crude product dehydrogenation nandrolone acetic ester (6), yield 93.4%, mp104-105 DEG C;
In described step (five): compound 5 is 1g: 12ml: 2.5ml: 0.015g with the ratio of the amount of methylene dichloride, acetic anhydride, triethylamine.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107188916A (en) * | 2017-07-05 | 2017-09-22 | 湖北工业大学 | A kind of preparation method of 6 dehydrogenation nandrolone acetate |
| CN107353318A (en) * | 2017-07-12 | 2017-11-17 | 湖北共同生物科技有限公司 | The preparation method of 6 dehydrogenation nandrolone acetates |
| CN108047299A (en) * | 2017-12-29 | 2018-05-18 | 广西万德药业有限公司 | The preparation method of canrenone important intermediate |
| CN108169220A (en) * | 2017-11-24 | 2018-06-15 | 武汉市农业科学院 | A kind of thick salt method and its production technology and application method based on horse serum cholinesterase |
| CN112094309A (en) * | 2020-09-28 | 2020-12-18 | 湖南新合新生物医药有限公司 | Preparation method of key intermediate of dehydronandrolone acetate |
| CN113045616A (en) * | 2021-03-23 | 2021-06-29 | 湖北共同药业股份有限公司 | Preparation method of 6-dehydronandrolone acetate |
| CN114634542A (en) * | 2022-03-30 | 2022-06-17 | 湖北武当安泰药业有限公司 | Preparation method of dehydronandrolone acetate |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107188916A (en) * | 2017-07-05 | 2017-09-22 | 湖北工业大学 | A kind of preparation method of 6 dehydrogenation nandrolone acetate |
| CN107353318A (en) * | 2017-07-12 | 2017-11-17 | 湖北共同生物科技有限公司 | The preparation method of 6 dehydrogenation nandrolone acetates |
| CN108169220A (en) * | 2017-11-24 | 2018-06-15 | 武汉市农业科学院 | A kind of thick salt method and its production technology and application method based on horse serum cholinesterase |
| CN108047299A (en) * | 2017-12-29 | 2018-05-18 | 广西万德药业有限公司 | The preparation method of canrenone important intermediate |
| CN108047299B (en) * | 2017-12-29 | 2021-11-09 | 广西万德药业有限公司 | Preparation method of important intermediate of canrenone |
| CN112094309A (en) * | 2020-09-28 | 2020-12-18 | 湖南新合新生物医药有限公司 | Preparation method of key intermediate of dehydronandrolone acetate |
| CN112094309B (en) * | 2020-09-28 | 2023-11-17 | 湖南新合新生物医药有限公司 | Preparation method of dehydronandrolone acetate key intermediate |
| CN113045616A (en) * | 2021-03-23 | 2021-06-29 | 湖北共同药业股份有限公司 | Preparation method of 6-dehydronandrolone acetate |
| CN113045616B (en) * | 2021-03-23 | 2022-06-14 | 湖北共同药业股份有限公司 | Preparation method of 6-dehydronandrolone acetate |
| CN114634542A (en) * | 2022-03-30 | 2022-06-17 | 湖北武当安泰药业有限公司 | Preparation method of dehydronandrolone acetate |
| CN114634542B (en) * | 2022-03-30 | 2022-11-25 | 湖北武当安泰药业有限公司 | Preparation method of dehydronandrolone acetate |
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