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Preparation method of 6-dehydronandrolone acetate

A technology of nandrolone acetate and acetic anhydride, applied in the directions of steroids, organic chemistry, etc., can solve the problems of low efficiency, high operation difficulty, low yield, etc., achieve less side reactions, avoid hydrolysis, and yield and the effect of improving purity

Active Publication Date: 2021-06-29
YICHENG GOTO PHARMA
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Problems solved by technology

[0003] The cost of synthesizing 6-dehydronandrolone acetate with nandrolone as raw material is relatively high, the diesterization reagent used has certain pollution, and the yield is not high; The raw material is to selectively protect the 3-position carbonyl with triethyl orthoformate under the catalysis of p-toluenesulfonic acid to obtain an etherification product, which is reduced by potassium borohydride, and then deprotected under the action of acetone and hydrochloric acid to obtain nandrolone. Nandrolone is through N-bromosuccinimide (NBS) bromination again through the diesterification of isopropenyl acetate, although the method that finally sloughs HBr with strong base and obtains 6-dehydronandrolone acetate reduces cost, However, in the first step of etherification reaction, the efficiency of selective protection of the 3-position carbonyl group by triethyl orthoformate is not high, and this method has a long route and high difficulty in operation

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  • Preparation method of 6-dehydronandrolone acetate
  • Preparation method of 6-dehydronandrolone acetate
  • Preparation method of 6-dehydronandrolone acetate

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[0027] The preparation method of described 6-dehydronandrolone acetate comprises the steps:

[0028] 1) Catalytic reaction of estro-4-ene-3,17-dione, acetic anhydride and p-toluenesulfonic acid to obtain compound 1;

[0029] 2) reducing compound 1, borohydride and aluminum chloride to obtain compound 2;

[0030] 3) react compound 2, N-bromosuccinimide and DMF to obtain compound 3 solution;

[0031] 4) adding compound 3 solution and base to obtain compound 4;

[0032] 5) Catalyzed reaction of compound 4, acetic anhydride, triethylamine and dichloromethane to obtain 6-dehydronandrolone acetate.

[0033] The mass volume ratio of estro-4-ene-3,17-dione, acetic anhydride and p-toluenesulfonic acid in step 1) of the present invention is preferably 0.8-1.2g: 2-4mL: 0.05-0.07g, more preferably 1g: 3mL: 0.06g; the temperature of the catalytic reaction is preferably 18-25°C, more preferably 20-22°C; the time of the catalytic reaction is preferably 1.5-2.5h, more preferably 2h.

[00...

Embodiment 1

[0043]Dissolve 1g of estro-4-ene-3,17-dione in 3mL of acetic anhydride, add 0.06g of p-toluenesulfonic acid, react at 22°C for 0.4h, the reaction solution precipitates a white solid, continue the reaction for 1h, then add 60mL of saturated The sodium carbonate solution was stirred for 0.6 h, and when the solid was in the form of powder in the solution, it was directly filtered, and the solid was dried to obtain Compound 1 in the form of off-white powder. Control the temperature of the reaction system at 8°C, add 0.06g of lithium borohydride, 0.06g of sodium borohydride, 0.15g of aluminum trichloride, and 20mL of methanol, react at this temperature for 0.5h, raise the temperature to 40°C and continue the reaction for 1.5h, take a sample for TLC After the reaction of the raw materials is complete, the system is added to NH at 5°C 4 Cl solution, the organic phase was separated, dried and concentrated to obtain compound 2 as a white solid. Compound 2 was dissolved in 10 mL of DMF...

Embodiment 2

[0046] Dissolve 0.9g of estro-4-ene-3,17-dione in 2.5mL of acetic anhydride, add 0.05g of p-toluenesulfonic acid, react at 20°C for 0.4h, the reaction solution precipitates a white solid, continue the reaction for 1h, then add 60 mL of saturated sodium carbonate solution was stirred for 1 h, and when the solid was in the form of powder in the solution, it was directly filtered, and the solid was dried to obtain Compound 1 in the form of off-white powder. Control the temperature of the reaction system at 12°C, add 0.12g of lithium borohydride, 0.1g of aluminum trichloride, and 20mL of methanol, react at this temperature for 0.5h, raise the temperature to 30°C and continue the reaction for 1h, take samples for TLC until the raw materials are completely reacted, and the system Added to 5 °C NH 4 Cl solution, the organic phase was separated, dried and concentrated to obtain compound 2 as a white solid. Dissolve compound 2 in 12 mL of DMF (not completely dissolved), then add dropw...

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Abstract

The invention belongs to the technical field of steroid drug intermediates, and provides a preparation method of 6-dehydronandrolone acetate. The preparation method comprises the following steps: carrying out a catalytic reaction on estra-4-ene-3,17-dione, acetic anhydride and p-toluenesulfonic acid to obtain a compound 1; carrying out a reduction reaction on the compound 1, hydroboron and aluminum trichloride to obtain a compound 2; subjecting the compound 2 and N-bromosuccinimide to reacting with DMF to obtain a solution of a compound 3; carrying out an addition reaction on the solution of the compound 3 and alkali to obtain a compound 4; and subjecting the compound 4, acetic anhydride, triethylamine and dichloromethane to a catalytic reaction to obtain 6-dehydronandrolone acetate. By adding borohydride and the aluminum trichloride in a reasonable ratio, hydrolysis of a 3-site ester group is effectively avoided, and side reactions are few; and meanwhile, the yield and the purity of a target product are remarkably improved by reasonably setting a synthesis route and controlling a reaction temperature.

Description

technical field [0001] The invention relates to the technical field of steroid drug intermediates, in particular to a preparation method of 6-dehydronandrolone acetate. Background technique [0002] Steroidal drugs play an important role in the prevention and treatment of diseases, including medicine, veterinary drugs and pesticides. Steroidal drugs currently on the market have many synthesis steps, complex reactions, obvious long-range effects of groups, low yields, and difficult separation and purification. The steroidal drug tibolone is a drug for treating menopausal or postmenopausal women's dysfunctional diseases. It can stabilize the hypothalamus and pituitary system of menopausal women, and can significantly inhibit the level of plasma follicle-stimulating hormone. The degree of inhibition of luteinizing hormone is relatively low. Light, does not affect prolactin, and can inhibit ovulation for women of childbearing age. The steroid drug fulvestrant is a drug used to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J1/00
CPCC07J1/0074
Inventor 潘高峰贺一君系祖斌
Owner YICHENG GOTO PHARMA
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