High-efficiency synthesis method of 6 alpha-bromo-carboxyandrost-4-ene-3,17-dione

A synthetic method and the technology of androsterol, which are applied in the field of organic chemistry and pharmaceutical synthesis, can solve the problems of ineffective separation of mixtures and difficulties in effective separation, and achieve the effects of cheap and easy-to-obtain reagents, high yield, and convenient operation

Inactive Publication Date: 2009-02-11
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It can be seen that it is difficult to effectively separate the 6β- and 6-α bromoisomers even by column chromatography, and the subsequent elution fractions are still a mixture with the same content of the two and cannot be effectively separated
Since then, the literature has continued to use this difficult method to obtain a trace amount of pure 6α-bromoandrost-4-ene-3,17-dione, and there is no other simple and high yield to obtain pure 6α-bromo-4-AD synthesis and Preparation [3]

Method used

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  • High-efficiency synthesis method of 6 alpha-bromo-carboxyandrost-4-ene-3,17-dione
  • High-efficiency synthesis method of 6 alpha-bromo-carboxyandrost-4-ene-3,17-dione
  • High-efficiency synthesis method of 6 alpha-bromo-carboxyandrost-4-ene-3,17-dione

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Experimental program
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Effect test

Embodiment 1

[0017] Preparation of 6α-bromo-androst-4-ene-3,17-dione

[0018] Configuration translocation method: strong acid as reagent and water as reaction medium

[0019] Add 120 mg of 6β-bromo-androst-4-ene-3,17-dione into 4 mL of concentrated hydrochloric acid, stir and react at room temperature for 21 hours, add 20 mL of ice water, filter, wash the cake with water until neutral, and dry at room temperature to obtain white 100 mg of powdery solid 6α-bromo-androst-4-ene-3,17-dione, yield 83.33%. Crude 1 H-NMR showed that the configuration of the 6α-bromo product was pure. Recrystallized with ethyl acetate to obtain fine product [α] 22 D =+143 0 (CHCl 3 ), mp: 171-172°C. Ms (m / z, %): 364 (M + , 6.79), 285 (M + -79,100); 1 HNMR δ (400HMz, CDCl 3 ): 0.92 (3H, s, 18-CH 3 ), 1.25 (3H, s, 19-CH 3 ), 4.91 (1H, m, 6-H), 6.45 (1H, s, 4-H).

Embodiment 2

[0021] Preparation of 6α-bromo-androst-4-ene-3,17-dione

[0022] Direct synthesis method: Br 2 / HOAc / THF is the reaction system

[0023]Androst-4-ene-3,17-dione 4.0g, 13.97mmol was dissolved in THF40mL, HOAc 4mL was added, bromine 2.33g, 13.97mmol was added dropwise at room temperature, the dropwise was completed in 15 minutes, and the reaction was basically completed after stirring for 15 minutes. Evaporate THF under reduced pressure at a bath temperature of 40-45°C, analyze with 80 mL of ice water, filter, wash the filter cake with water until it is neutral, and dry it by infrared to obtain the crude yellow solid product 6α-bromo-androst-4-ene- 3, 17-diketone 4.96g, yield: 97.2%: mp: 164-165°C turns black and decomposes, crude product determination 1 H-NMR showed that the configuration of the 6α-bromo product was pure. Ethyl acetate recrystallized to obtain fine product[α] 22 D =143 0 (CHCl 3 ), mp: 171-172°C. Ms (m / z, %): 364 (M + , 6.79), 285 (M + -79,100); 1 H ...

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Abstract

The invention pertains to chemical and medicine synthesis field and relates to an indirect synthesis method and a direct synthesis method of a compound 6 alpha -bromo-androstane-4-ene-3, 17-dione. The methods are: (1) the compound 6 beta-bromo-androstane-4-ene-3, 17-dione is directly transformed structurally by strong acid in aqueous medium, and a configuration pure 6 alpha-bromo-androstane-4-ene-3, 17-dione is obtained with a high yield; (2) androstane-4-ene-3, 17-dione is used as the material to synthesize 6 alpha -bromo-androstane-4-ene-3, 17-dione in a high yield with the condition of Br2/HOAc/THF. The products prepared by both methods are identical; the spatial configuration is confirmed by X-diffraction, the synthesis methods of the invention have the advantages of moderate and convenient reaction conditions, cheap and available agents, convenient operation, good reproducibility and high yield. The methods of the invention can be used as a source of reference and be used in the preparation and synthesis of the 6 alpha-bromides of steroids with 4-ene- 3-one system.

Description

[0001] This application is the divisional case of the invention name: efficient synthesis method of 6α-bromo-androst-4-ene-3,17-dione, application number: 2006101473084, application date: December 14, 2006. technical field [0002] The invention belongs to the field of organic chemistry and medicine synthesis, and specifically relates to an efficient synthesis method of compound 6α-bromo-androst-4-ene-3,17-dione. Background technique [0003] Aromatase (Aromatase) is an important enzyme in the biosynthesis of estrogen in vivo. Aromatase inhibitors have become an important area of ​​research for drugs that treat estrogen-associated cancers. A series of bromo-4-en-3-one steroid compounds have been reported in the literature, such as: 6α and 6β-bromo-androst-4-ene-3,17-dione and its 2,2-dimethyl derivatives and other 6-bromo compounds have significant aromatase inhibitory activity, but the pharmacological mechanisms of the two are different [ 1. Francis L. Bellino, Syed S.H. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J1/00
Inventor 夏鹏陈瑛
Owner FUDAN UNIV
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