CN113045616A - Preparation method of 6-dehydronandrolone acetate - Google Patents
Preparation method of 6-dehydronandrolone acetate Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
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- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
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Abstract
The invention belongs to the technical field of steroid drug intermediates. The invention provides a preparation method of 6-dehydro nandrolone acetate, which comprises the following steps: carrying out catalytic reaction on estra-4-ene-3, 17-dione, acetic anhydride and p-toluenesulfonic acid to obtain a compound 1; carrying out reduction reaction on the compound 1, borohydride and aluminum trichloride to obtain a compound 2; reacting the compound 2, N-bromosuccinimide with DMF to obtain a compound 3 solution; carrying out addition reaction on the compound 3 solution and alkali to obtain a compound 4; and carrying out catalytic reaction on the compound 4, acetic anhydride, triethylamine and dichloromethane to obtain 6-dehydronandrolone acetate. According to the invention, by adding borohydride and aluminum trichloride in a reasonable proportion, hydrolysis of 3-bit ester group is effectively avoided, and side reactions are less; meanwhile, the yield and the purity of the target product are obviously improved by reasonably setting the synthesis route and controlling the reaction temperature.
Description
Technical Field
The invention relates to the technical field of steroid drug intermediates, in particular to a preparation method of 6-dehydronandrolone acetate.
Background
Steroid drugs play an important role in preventing and treating diseases, including medicines, veterinary medicines and pesticides, and the steroid drugs in the current market have the advantages of multiple synthesis steps, complex reaction, obvious long-range effect of radicals, low yield and difficult separation and purification. The steroid medicine tibolone is a medicine for curing the functional disorder disease of menopausal women after menopause or operation, it can make hypothalamus pituitary system of climacteric women stable, can obviously inhibit the level of plasma follicle-stimulating hormone, and has the functions of inhibiting ovulation of women of childbearing age, and its inhibition extent is light, and does not affect prolactin. The steroid drug fulvestrant is a drug used for treating breast cancer. 6-dehydronandrolone acetate is a key intermediate for synthesizing tibolone and fulvestrant.
The 6-dehydro nandrolone acetate synthesized by taking nandrolone as a raw material has higher cost, the used diester reagent has certain pollution, and the yield is not high; according to the method, estra-4-alkene-3, 17-diketone is used as a raw material, carbonyl at the 3-position is selectively protected by triethyl orthoformate under the catalysis of p-toluenesulfonic acid to obtain an etherified product, the product is reduced by potassium borohydride and then deprotected under the action of acetone and hydrochloric acid to obtain nandrolone, the nandrolone is subjected to isopropenyl acetate double esterification and then is brominated by N-bromosuccinimide (NBS), and finally HBr is removed by strong base to obtain 6-dehydronandrolone acetate.
Therefore, the research and development of the preparation method of the 6-dehydronandrolone acetate, which can improve the reaction efficiency and yield and reduce the cost, has very important significance.
Disclosure of Invention
The invention aims to provide a preparation method of 6-dehydronandrolone acetate aiming at the defects of the prior art. According to the invention, borohydride and aluminum trichloride are added into the reduction system in a reasonable proportion, so that hydrolysis of 3-position ester group is effectively avoided, side reaction is less, yield and purity of a target product are obviously improved, and meanwhile, through reasonable setting of a synthesis route and control of reaction temperature, yield of the obtained 6-dehydronandrolone acetate is more than or equal to 98%, and purity is more than or equal to 98%.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of 6-dehydro nandrolone acetate, which takes estra-4-alkene-3, 17-diketone as a raw material to prepare the 6-dehydro nandrolone acetate through the following route:
the preparation method of the 6-dehydronandrolone acetate comprises the following steps:
1) carrying out catalytic reaction on estra-4-ene-3, 17-dione, acetic anhydride and p-toluenesulfonic acid to obtain a compound 1;
2) carrying out reduction reaction on the compound 1, borohydride and aluminum trichloride to obtain a compound 2;
3) reacting the compound 2, N-bromosuccinimide with DMF to obtain a compound 3 solution;
4) carrying out addition reaction on the compound 3 solution and alkali to obtain a compound 4;
5) and carrying out catalytic reaction on the compound 4, acetic anhydride, triethylamine and dichloromethane to obtain 6-dehydronandrolone acetate.
Preferably, the mass-volume ratio of the estra-4-ene-3, 17-dione, the acetic anhydride and the p-toluenesulfonic acid in the step 1) is 0.8-1.2 g: 2-4 mL: 0.05-0.07 g; the temperature of the catalytic reaction is 18-25 ℃, and the time is 1.5-2.5 h.
Preferably, the mass ratio of the borohydride to the aluminum trichloride in the step 2) is 0.1-0.15: 0.1 to 0.25; the mass ratio of the borohydride to the estra-4-ene-3, 17-dione in the step 1) is 0.1-0.15: 0.8-1.2.
Preferably, the borohydride in the step 2) is one or more of lithium borohydride, sodium borohydride and potassium borohydride; the temperature of the reduction reaction is 8-45 ℃, and the time is 1-2.5 h.
Preferably, the mass-volume ratio of the N-bromosuccinimide to the DMF in the step 3) is 1-3 g: 60-80 mL; the mass ratio of the N-bromosuccinimide to the estra-4-ene-3, 17-dione in the step 1) is 1-3: 3 to 5.
Preferably, the reaction temperature in the step 3) is-4-5 ℃, and the reaction time is 1-3 h.
Preferably, the alkali in the step 4) comprises carbonate and bromide in a mass ratio of 1: 1-1.5; the carbonate is lithium carbonate, sodium carbonate or potassium carbonate; the bromide is lithium bromide, sodium bromide or potassium bromide.
Preferably, the mass ratio of the base in the step 4) to the estra-4-ene-3, 17-dione in the step 1) is 0.8-1.2: 1; the temperature of the addition reaction is 50-85 ℃, and the time is 5-7 h.
Preferably, the mass-to-volume ratio of the acetic anhydride, the triethylamine and the dichloromethane in the step 5) is 2-3 mL: 0.02-0.025 g, 12-14 mL; the mass ratio of the triethylamine to the estra-4-ene-3, 17-dione in the step 1) is 0.02-0.025: 1; the temperature of the catalytic reaction is 55-70 ℃, and the time is 0.5-1 h.
The invention has the beneficial effects that:
in the reduction system, the borohydride and the aluminum trichloride are added in a reasonable proportion, so that the hydrolysis of the 3-bit ester group is effectively avoided, and the side reaction is less; meanwhile, the yield and the purity of the target product are obviously improved by reasonably setting the synthesis route and controlling the reaction temperature.
Detailed Description
The invention provides a preparation method of 6-dehydro nandrolone acetate, which takes estra-4-alkene-3, 17-diketone as a raw material to prepare the 6-dehydro nandrolone acetate through the following route:
the preparation method of the 6-dehydronandrolone acetate comprises the following steps:
1) carrying out catalytic reaction on estra-4-ene-3, 17-dione, acetic anhydride and p-toluenesulfonic acid to obtain a compound 1;
2) carrying out reduction reaction on the compound 1, borohydride and aluminum trichloride to obtain a compound 2;
3) reacting the compound 2, N-bromosuccinimide with DMF to obtain a compound 3 solution;
4) carrying out addition reaction on the compound 3 solution and alkali to obtain a compound 4;
5) and carrying out catalytic reaction on the compound 4, acetic anhydride, triethylamine and dichloromethane to obtain 6-dehydronandrolone acetate.
The mass-volume ratio of the estra-4-ene-3, 17-dione, the acetic anhydride and the p-toluenesulfonic acid in the step 1) is preferably 0.8-1.2 g: 2-4 mL: 0.05 to 0.07g, more preferably 1 g: 3mL of: 0.06 g; the temperature of the catalytic reaction is preferably 18-25 ℃, and more preferably 20-22 ℃; the time of the catalytic reaction is preferably 1.5-2.5 h, and more preferably 2 h.
The mass ratio of the borohydride to the aluminum trichloride in the step 2) is preferably 0.1-0.15: 0.1 to 0.25, more preferably 0.15: 0.2; the mass ratio of the borohydride to the estra-4-ene-3, 17-dione in the step 1) is preferably 0.1-0.15: 0.8-1.2, and more preferably 0.12-0.14: 1.
The borohydride in the step 2) of the invention is preferably one or more of lithium borohydride, sodium borohydride and potassium borohydride; further preferably selecting lithium borohydride and sodium borohydride with the mass ratio of 1-2: 1-2; the temperature of the reduction reaction is preferably 8-45 ℃, and is further preferably 20-40 ℃; the time of the reduction reaction is preferably 1 to 2.5 hours, and more preferably 1.5 to 2 hours.
The mass-volume ratio of the N-bromosuccinimide to the DMF in the step 3) of the invention is preferably 1-3 g: 60-80 mL, and more preferably 1.5-2.5 g: 65-75 mL; the mass ratio of the N-bromosuccinimide to the estra-4-ene-3, 17-dione in the step 1) is preferably 1-3: 3 to 5, and more preferably 2: 4.
The reaction temperature in the step 3) of the invention is preferably-4-5 ℃, and more preferably 0-2 ℃; the reaction time is preferably 1-3 h, and more preferably 2 h; the reaction is preferably that the compound 2 is partially dissolved in DMF solution, and then the DMF solution in which the N-bromosuccinimide is dissolved is dripped; the preferred DMF solution for dissolving the N-bromosuccinimide is 40-50% of the total volume of the DMF solution; more preferably 42 to 47%.
The base in step 4) of the present invention preferably includes carbonate and bromide; the mass ratio of the carbonate to the bromide is preferably 1: 1-1.5, and more preferably 1: 1.2-1.3; the carbonate is preferably lithium carbonate, sodium carbonate or potassium carbonate; the bromide is preferably lithium bromide, sodium bromide or potassium bromide.
The mass ratio of the base in the step 4) to the estra-4-ene-3, 17-dione in the step 1) is preferably 0.8-1.2: 1, more preferably 1: 1; the temperature of the addition reaction is preferably 50-85 ℃, more preferably 60-80 ℃, and more preferably 70 ℃; the time of the addition reaction is preferably 5-7 h, and more preferably 6 h.
The mass-volume ratio of acetic anhydride, triethylamine and dichloromethane in the step 5) of the invention is preferably 2-3 mL: 0.02 to 0.025g, 12 to 14mL, more preferably 2.5 mL: 0.02g, 13 mL; the mass ratio of the triethylamine to the estra-4-ene-3, 17-dione in the step 1) is preferably 0.02-0.025: 1, more preferably 0.035: 1; the temperature of the catalytic reaction is preferably 55-70 ℃, and further preferably 60-65 ℃; the time of the catalytic reaction is preferably 0.5-1 h, and more preferably 0.75 h.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Dissolving 1g of estra-4-ene-3, 17-dione in 3mL of acetic anhydride, adding 0.06g of p-toluenesulfonic acid, reacting at 22 ℃ for 0.4h to separate out a white solid, continuing to react for 1h, adding 60mL of saturated sodium carbonate solution, stirring for 0.6h, directly filtering when the solid is in a powder state in the solution, and airing the solid to obtain the white powdery compound 1. Controlling the temperature of the reaction system to be 8 ℃, adding 0.06g of lithium borohydride, 0.06g of sodium borohydride, 0.15g of aluminum trichloride and 20mL of methanol, reacting for 0.5h at the temperature, heating to 40 ℃, continuing to react for 1.5h, sampling TLC until the raw materials react completely, adding the system to NH at 5 DEG C4And (3) separating an organic phase from the Cl solution, drying and concentrating to obtain a white solid compound 2. Dissolving the compound 2 in 10ml DMF (not completely dissolved), dripping DMF solution for dissolving N-bromosuccinimide (0.5g of N-bromosuccinimide is dissolved in 8ml DMF) at 0 ℃, and keeping the temperature for 1.5h after dripping for 0.5h to obtain a compound 3 solution. To the compound 3 solution was added 0.5g of sodium bisulfite and stirred for 20min, followed by addition of 0.45g of sodium carbonate and 0.55g of sodium bromide, and the temperature was raised to 70 ℃ to react for 6h until the bromide spot disappeared. The obtained suspensionCooling the floating object to room temperature, dropwise adding a small amount of acetic acid and seed crystals, separating solids, washing the obtained filter cake with 2mL of mixed solution of isopropanol and water, adding 20mL of isopropanol into the crude product, slowly dropwise adding water to fully precipitate the product after the solution turns brown, washing the filtered filter cake with a mixed solution of isopropanol and water in a volume ratio of 1:1, and drying to obtain a white solid compound 4. Adding 2.5mL of acetic anhydride, 0.02g of triethylamine and 13mL of dichloromethane into the compound 4, reacting at 60 ℃ for 0.75h, washing with a saturated sodium bicarbonate solution to be neutral, separating an organic layer after no bubble is generated, washing the organic layer with saturated saline and water for 3 times respectively, drying and concentrating to obtain a white solid 6-dehydronandrolone acetate.
The yield of 6-dehydronandrolone acetate obtained in example 1 was 99.2%, and the purity was not less than 99%.
Example 2
Dissolving 0.9g of estra-4-ene-3, 17-dione in 2.5mL of acetic anhydride, adding 0.05g of p-toluenesulfonic acid, reacting at 20 ℃ for 0.4h to separate out a white solid, continuing to react for 1h, adding 60mL of saturated sodium carbonate solution, stirring for 1h, directly filtering when the solid is in a powder state in the solution, and airing the solid to obtain the compound 1 in a white powder state. Controlling the temperature of a reaction system to be 12 ℃, adding 0.12g of lithium borohydride, 0.1g of aluminum trichloride and 20mL of methanol, reacting for 0.5h at the temperature, heating to 30 ℃, continuing to react for 1h, sampling TLC until the raw materials react completely, adding the system to NH at 5 DEG C4And (3) separating an organic phase from the Cl solution, drying and concentrating to obtain a white solid compound 2. Dissolving the compound 2 in 12mL of DMF (not completely dissolved), dropwise adding a DMF solution for dissolving N-bromosuccinimide (0.4g of N-bromosuccinimide dissolved in 8mL of DMF) at 2 ℃, and continuously preserving the heat for 1h after the dropwise adding is finished for 0.5h to obtain a compound 3 solution. To the compound 3 solution was added 0.5g of sodium bisulfite and stirred for 20min, followed by addition of 0.35g of sodium carbonate and 0.35g of sodium bromide, and the temperature was raised to 80 ℃ to react for 5h until the bromide spot disappeared. Cooling the obtained suspended matter to room temperature, dripping a small amount of acetic acid and seed crystal, separating solid, washing the obtained filter cake with 2mL of mixed solution of dimethyl formamide and dimethyl formamide, adding 20mL of isopropanol into the crude product, slowly dripping water to fully precipitate the product after the solution turns brown, and filtering the obtained filter cakeWashing the mixed solution of isopropanol and water in a volume ratio of 1:1, and drying to obtain a white solid compound 4. Adding 2mL of acetic anhydride, 0.02g of triethylamine and 12mL of dichloromethane into the compound 4, reacting at 55 ℃ for 1h, washing the mixture by using a saturated sodium bicarbonate solution until the mixture is neutral, separating an organic layer after no bubbles are generated, washing the organic layer by using saturated saline and water for 3 times respectively, and drying and concentrating the organic layer to obtain a white solid 6-dehydronanone acetate.
The yield of the 6-dehydronandrolone acetate obtained in example 2 is 98%, and the purity is more than or equal to 98%.
Example 3
Dissolving 1.1g of estra-4-ene-3, 17-dione in 3.5mL of acetic anhydride, adding 0.07g of p-toluenesulfonic acid, reacting at 23 ℃ for 0.3h to separate out a white solid, continuing to react for 1h, adding 60mL of saturated sodium carbonate solution, stirring for 0.5h, directly filtering when the solid is in a powder state in the solution, and airing the solid to obtain the white powdery compound 1. Controlling the temperature of the reaction system to be 10 ℃, adding 0.16g of potassium borohydride, 0.25g of aluminum trichloride and 20mL of methanol, reacting for 0.5h at the temperature, heating to 40 ℃, continuing to react for 2h, sampling TLC until the raw materials react completely, adding the system to NH at 5 DEG C4And (3) separating an organic phase from the Cl solution, drying and concentrating to obtain a white solid compound 2. Dissolving the compound 2 in 28mL of DMF (not completely dissolved), then dropwise adding a DMF solution in which N-bromosuccinimide is dissolved (0.82g of N-bromosuccinimide is dissolved in 28mL of DMF) at-2 ℃, and after dropwise adding for 1h, continuously preserving the temperature for 1.5h to obtain a compound 3 solution. To the compound 3 solution was added 0.7g of sodium bisulfite and stirred for 20min, followed by addition of 0.5g of sodium carbonate and 0.7g of sodium bromide, and the temperature was raised to 60 ℃ to react for 7h until the bromide spot disappeared. Cooling the obtained suspended matter to room temperature, dropwise adding a small amount of acetic acid and seed crystals, separating solids, washing the obtained filter cake with 2mL of mixed solution of isopropanol and water, adding 20mL of isopropanol into the crude product, slowly dropwise adding water to fully precipitate the product after the solution turns brown, washing the filtered filter cake with a mixed solution of isopropanol and water in a volume ratio of 1:1, and drying to obtain a white solid compound 4. Adding 3mL of acetic anhydride, 0.025g of triethylamine and 14mL of dichloromethane into the compound 4, reacting at 65 ℃ for 0.5h, and washing with saturated sodium bicarbonate solution to be neutralAfter no bubble was generated, the organic layer was separated, washed with saturated brine and water for 3 times, dried and concentrated to obtain 6-dehydronandrolone acetate as a white solid.
The yield of the 6-dehydronandrolone acetate obtained in example 3 is 98.5%, and the purity is not less than 99%.
Comparative example 1
Estra-4-ene-3, 17-dione, acetic anhydride and p-toluenesulfonic acid were reacted at 15 ℃ under the same conditions as in example 1.
The 6-dehydronandrolone acetate obtained in comparative example 1 was in 92% yield and 92% purity.
Comparative example 2
Estra-4-ene-3, 17-dione, acetic anhydride and p-toluenesulfonic acid were reacted at 35 ℃ under the same conditions as in example 1.
The 6-dehydronandrolone acetate obtained in comparative example 2 had a yield of 87% and a purity of 88%.
Comparative example 3
The reaction system of Compound 1 was charged with 0.12g of lithium borohydride and 0.06g of aluminum trichloride, and the other conditions were the same as in example 1.
The 6-dehydronandrolone acetate obtained in comparative example 3 had a yield of 89% and a purity of 88%.
Comparative example 4
Acetic anhydride, triethylamine and dichloromethane were added to compound 4, and the reaction was carried out at 45 ℃ under the same conditions as in example 1.
The 6-dehydronandrolone acetate obtained in comparative example 4 was obtained in 90% yield and 90% purity.
Comparative example 5
Acetic anhydride, triethylamine and dichloromethane were added to compound 4, and the reaction was carried out at 80 ℃ under the same conditions as in example 1.
The 6-dehydronandrolone acetate obtained in comparative example 5 was in 92% yield and 92% purity.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. The preparation method of 6-dehydro nandrolone acetate is characterized in that estra-4-ene-3, 17-diketone is used as a raw material, and the 6-dehydro nandrolone acetate is prepared by the following route:
the preparation method of the 6-dehydronandrolone acetate comprises the following steps:
1) carrying out catalytic reaction on estra-4-ene-3, 17-dione, acetic anhydride and p-toluenesulfonic acid to obtain a compound 1;
2) carrying out reduction reaction on the compound 1, borohydride and aluminum trichloride to obtain a compound 2;
3) reacting the compound 2, N-bromosuccinimide with DMF to obtain a compound 3 solution;
4) carrying out addition reaction on the compound 3 solution and alkali to obtain a compound 4;
5) and carrying out catalytic reaction on the compound 4, acetic anhydride, triethylamine and dichloromethane to obtain 6-dehydronandrolone acetate.
2. The preparation method according to claim 1, wherein the mass-to-volume ratio of the estra-4-ene-3, 17-dione, acetic anhydride and p-toluenesulfonic acid in step 1) is 0.8-1.2 g: 2-4 mL: 0.05-0.07 g; the temperature of the catalytic reaction is 18-25 ℃, and the time is 1.5-2.5 h.
3. The preparation method according to claim 1 or 2, wherein the mass ratio of the borohydride to the aluminum trichloride in the step 2) is 0.1-0.15: 0.1 to 0.25; the mass ratio of the borohydride to the estra-4-ene-3, 17-dione in the step 1) is 0.1-0.15: 0.8-1.2.
4. The preparation method according to claim 3, wherein the borohydride in step 2) is one or more of lithium borohydride, sodium borohydride and potassium borohydride; the temperature of the reduction reaction is 8-45 ℃, and the time is 1-2.5 h.
5. The preparation method of claim 4, wherein the mass-to-volume ratio of the N-bromosuccinimide to the DMF in the step 3) is 1-3 g: 60-80 mL; the mass ratio of the N-bromosuccinimide to the estra-4-ene-3, 17-dione in the step 1) is 1-3: 3 to 5.
6. The preparation method of claim 5, wherein the reaction temperature in the step 3) is-4-5 ℃ and the reaction time is 1-3 h.
7. The preparation method according to claim 5 or 6, wherein the base in the step 4) comprises carbonate and bromide in a mass ratio of 1: 1-1.5; the carbonate is lithium carbonate, sodium carbonate or potassium carbonate; the bromide is lithium bromide, sodium bromide or potassium bromide.
8. The preparation method according to claim 7, wherein the mass ratio of the base in step 4) to the estra-4-ene-3, 17-dione in step 1) is 0.8 to 1.2: 1; the temperature of the addition reaction is 50-85 ℃, and the time is 5-7 h.
9. The preparation method according to claim 8, wherein the mass-to-volume ratio of the acetic anhydride, the triethylamine and the dichloromethane in the step 5) is 2-3 mL: 0.02-0.025 g, 12-14 mL; the mass ratio of the triethylamine to the estra-4-ene-3, 17-dione in the step 1) is 0.02-0.025: 1; the temperature of the catalytic reaction is 55-70 ℃, and the time is 0.5-1 h.
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| 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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| CN102391341A (en) * | 2011-08-09 | 2012-03-28 | 福建省微生物研究所 | Method for preparing 6,7-dehydro-17beta-hydrocarbon acyloxy nandrolone |
| CN104292285A (en) * | 2014-09-30 | 2015-01-21 | 湖北三晶生物科技有限公司 | Process for synthesizing high-content dehydronandrolon acetate |
| 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 |
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| CN102391341A (en) * | 2011-08-09 | 2012-03-28 | 福建省微生物研究所 | Method for preparing 6,7-dehydro-17beta-hydrocarbon acyloxy nandrolone |
| CN104292285A (en) * | 2014-09-30 | 2015-01-21 | 湖北三晶生物科技有限公司 | Process for synthesizing high-content dehydronandrolon acetate |
| 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 |
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| 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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