The preparation method of 6-methylene-17α-hydroxyprogesterone acetate

A technology of hydroxyprogesterone acetate and hydroxyprogesterone acetate, which is applied in the field of preparation of 6-methylene-17α-hydroxyprogesterone acetate, can solve the problems of low yield, cumbersome post-processing, incomplete reaction of raw materials, etc. problems, to achieve the effect of high yield, high intensity, and less by-products

Inactive Publication Date: 2020-06-23
杭州弘任医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above-mentioned inventions all need to acetylate 17α-hydroxyprogesterone first, and then carry out Mannich reaction after etherification with triethyl orthoformate. In the later stage of the reaction, the pH of the system changes, resulting in incomplete reaction of raw materials and cumbersome post-processing. Disadvantages of low yield

Method used

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  • The preparation method of 6-methylene-17α-hydroxyprogesterone acetate
  • The preparation method of 6-methylene-17α-hydroxyprogesterone acetate
  • The preparation method of 6-methylene-17α-hydroxyprogesterone acetate

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Effect test

Embodiment 1

[0027] 1) Acylation reaction of 17α-hydroxyprogesterone with sulfuric acid of 0.025 times the amount of the substance and acetic anhydride of 3 times the amount of the substance in tetrahydrofuran of 2 times the mass, the reaction temperature is 40 ° C, and the reaction time is 3 hours to obtain Compound of formula III;

[0028] 2) In another reaction flask, dimethylamine and formaldehyde are reacted to generate the Mannich reagent, and then the Mannich reagent of 1 times the amount of the substance is added to the reaction flask of the compound of the above formula III to continue the reaction for 1 hour, the reaction temperature 50°C until the reaction is complete to obtain tertiary amine compound IV of 6-methylene-17α-hydroxyprogesterone acetate;

[0029] 3) Hydrochloric acid was added dropwise in an amount twice as much as the substance to continue the reaction, the reaction temperature was -10°C, and the reaction time was 4 hours. The product 6-methylene-17α-hydroxyproge...

Embodiment 2

[0031] 1) Acylation reaction of 17α-hydroxyprogesterone with p-toluenesulfonic acid of 0.05 times the amount of the substance and acetic anhydride of 15 times the amount of the substance, the reaction temperature is 120 ° C, and the reaction time is 4 hours to obtain the compound of formula III ;

[0032] 2) In another reaction flask, dimethylamine and paraformaldehyde are reacted in 6 times the mass of dioxane to generate the Mannich reagent, and then the Mannich reagent of 1.5 times the amount of the substance is added to the above formula III Continue to react in the reaction flask of the compound for 6 hours at a reaction temperature of 10°C until the reaction is complete to obtain tertiary amine compound IV of 6-methylene-17α-hydroxyprogesterone acetate;

[0033] 3) Adding phosphoric acid in an amount 10 times that of the substance dropwise to continue the reaction, the reaction temperature is 70° C., and the reaction time is 5 hours. The product 6-methylene-17α-hydroxyp...

Embodiment 3

[0035] 1) Acylation reaction of 17α-hydroxyprogesterone with phosphoric acid of 0.1 times the amount of the substance and acetic anhydride of 8 times the amount of the substance, the reaction temperature is 60 ° C, and the reaction time is 4 hours to obtain the compound of formula III;

[0036] 2) In another reaction flask, N-methylaniline and formaldehyde are reacted in ethylene glycol dimethyl ether of 10 times the mass to generate the Mannich reagent, and then the Mannich reagent of 1.4 times the amount of the substance is added to the above-mentioned Continue to react in the reaction flask of the compound of formula III for 3 hours at a reaction temperature of 30° C. until the reaction is complete to obtain tertiary amine compound IV of 6-methylene-17α-hydroxyprogesterone acetate;

[0037] 3) Adding sulfuric acid in an amount 5 times that of the substance dropwise to continue the reaction, the reaction temperature is 20° C., and the reaction time is 2 hours. The product 6-...

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Abstract

The invention discloses a preparation method of 6-methylene-17alpha-hydroxyprogesterone acetate. The preparation method comprises the following steps: (1) enabling 17alpha-hydroxyl progesterone to have acylation reaction with 0.025 to 0.1 time of amount of substance of catalyst and 1 to 10 times of amount of substance of acetic anhydride, then adding 1 to 1.5 times of amount of substance of Mannich reagent into 2 to 10 times of mass ratio of solvent to have reaction, wherein the reaction temperature is -10 DEG C to 60 DEG C, the reaction time is 3 to 10 hours, and obtaining 6-methylene-17alpha-hydroxyprogesterone acetate tertiary amine; and (2) enabling the 6-methylene-17alpha-hydroxyprogesterone acetate tertiary amine to have reaction with 1 to 10 times of amount of substance of acid, wherein the reaction temperature is -10 DEG C to 70 DEG C, the reaction time is 1 to 5 hours, thus obtaining the product 6-methylene-17alpha-hydroxyprogesterone acetate. By adopting the preparation method, medroxyprogesterone and megestrol acetate progestational hormone can be conveniently prepared. The preparation method has the characteristics of good quality, high yield and easiness in industrialization, and has important significance on preparing sterides drugs.

Description

technical field [0001] The invention relates to a preparation method of 6-methylene-17α-hydroxyprogesterone acetate. Background technique [0002] Medroxyprogesterone acetate and megestrol acetate are synthetic luteal progestogens, widely used in the treatment of irregular menstruation, dysfunctional uterine bleeding and endometriosis. Injections can be used as long-acting contraceptives, and in large doses to treat breast cancer, among other things. Its key intermediate is 6-methylene-17α-hydroxyprogesterone acetate. At present, the main methods for introducing methine are the following patents. [0003] US200912321 carries out etherification reaction with 17α-hydroxyprogesterone acetate under the catalysis of p-toluenesulfonic acid in ethylene glycol dimethyl ether and triethyl orthoformate, and then ethylene glycol dimethyl with N-methylaniline and formaldehyde Complete reaction of ether solution, water analysis, extraction with isopropyl ether, hydrochloric acid hydro...

Claims

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Application Information

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Patent Type & AuthorityPatents(China)
IPC IPC(8): C07J7/00
CPCC07J7/0045
Inventor王海清张英方监飞
Owner杭州弘任医药科技有限公司