Method for synthesizing 2-methoxy estradiol

A technology of methoxyestradiol and a synthesis method, which is applied in the field of synthesizing compound 2-methoxyestradiol, can solve the problem of difficulty in distinguishing between substrate and product spots, affecting the quality reaction of intermediates, difficult recycling of DMF, etc. problems, to achieve the effect of saving reagents, simplifying operation, and improving yield

Inactive Publication Date: 2008-04-16
FUDAN UNIV
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Problems solved by technology

[0009] 1. In the step 2a synthesized from 1a, the literature reports that a large amount of pyridine is used as a solvent, which has a great impact on environmental pollution, and it takes 16 hours to complete, which takes a long time
[0010] 2. In the step of synthesizing 3a from 2a, the TLC developer (1% acetone / CH 2 Cl 2 ), it is difficult to distinguish between substrate and product spots, and it is easy to cause the reaction end point to be difficult to control, affecting the quality of intermediates and subsequent reactions
[0011] 3. In the step of 4a synthesized from 3a, the original document reports that a large amount of DMF is used as the reaction solvent, and the DMF after post-treatment and water analysis is difficult to recycle, which is not conducive to environmental protection. It is necessary to add bromobenzyl / anhydrous sodium carbonate twice in the reaction, which will take a long time The reaction can only be completed by heating at 60°C for a long time, which consumes a lot of energy and is difficult to control, and the operation is complicated

Method used

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  • Method for synthesizing 2-methoxy estradiol
  • Method for synthesizing 2-methoxy estradiol
  • Method for synthesizing 2-methoxy estradiol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: 1,3,5(10)-triene-3,17β-estradiol diethyl ester

[0032] Add 500mg (1.84mmol) of estradiol and 1.51g (18.36mmol) NaOAc to 10.35mL (110.14mmol) of Ac 2 O, heated to reflux. The initial reaction solution was a white suspension, which was basically dissolved after heating for five minutes, and a large amount of white foamy substances were produced. Heating at reflux for 30min was complete. The acetic anhydride was removed under reduced pressure and washed with CHCl 3 Extraction reaction liquid, saturated Na 2 CO 3 (aq.) Wash twice, then wash with water until neutral. Combined aqueous phase, CHCl 3 Reverse phase extraction twice. The organic phases were combined and the solvent was removed to give 830 mg of a white solid. Hot methanol recrystallization gave 649.75mg of white scaly crystals, mp: 120-122°C, yield 99.14%. Ms (m / z, 100%): 356 (M, 8.91), 314 (basepeak, 100%)

[0033] 1 H-NMR (CDCl 3 ): δ0.83(s, 3H, C 18 -H), 2.05(s, 3H, C 17 -OCOCH 3 ), 2....

Embodiment 2

[0034] Example 2: 2-acetyl-3 benzyloxy-1,3,5(10)-triene-17β-dihydroxy-17-acetate Weigh 4.21g (11.8mmol) 2-acetyl-1 , 3,5(10)-triene-3,17β-alcohol acetate was dissolved in 108mL CH 2 Cl 2 Turn into yellow clear liquid, add 2.69g (11.80mmol) TEBA, dissolve completely. Weigh 16.87g of NaOH to prepare a 20% NaOH solution and add it to the reaction solution. Then measure 4.22mL (35.40mmol) PhCH 2 Br was added to the reaction solution. The reaction solution was separated into layers and stirred vigorously at room temperature for 72 hours. TLC (benzene:acetone 30:2) showed that the reaction was complete. Add 100 mL of ice water, and continue stirring for 1 hour in the ice water bath. use CH 2 Cl 2 Extract three times, combine the organic phase and wash three times with water. The crude weight of the dried solvent was 5.82 g. Recrystallization from hot methanol gave 3.14g, mp: 159-160°C. Recover the mother liquor to obtain: 1.43g, mp: 158-160°C, and dry the mother liquor: 0...

Embodiment 3

[0037] Example 3: 2-methoxy-3-benzyloxy-1,3,5(10)-triene-17β-estradiol

[0038] Weigh 1.00g (2.16mmol) 3-benzyloxy-1,3,5(10)-triene-2,17β-diol diacetate, dissolve in 68mL C 2 h 5 OH, into a white suspension. Add 224.72mg (5.62mmol) of NaOH, and the reaction liquid becomes clear to light red rapidly after heating. Heating to reflux for 1h, TLC showed that the reaction was complete. Ethanol was removed under reduced pressure. Add 60mL CH directly to the reaction solution without separation 2 Cl 2 , 50mL H 2 O, 492.68mg (2.16mmol) TEBA, 1.00mL dimethyl sulfate, add 2.50g NaOH, the measured pH=14. After 4 hours of reaction, TLC (benzene:acetone 8:2) showed that the reaction was complete. Wash to neutral, CH 2 Cl 2 Extract twice, combine the organic phases, and pull dry crude weight 1.43g. 0.75 g of 7a was obtained by using petroleum ether: ethyl acetate 20:4 as developing solvent to obtain 0.75 g of 7a, mp: 98°C-100°C. The yield was 88.06%. Ethyl acetate was recrystal...

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Abstract

The present invention belongs to the field of organic chemistry and drug synthesis, and relates to a synthetic method of 2-methoxyestradiol. The present invention adopts estradiol as the original raw material, which undergoes six reactions including acylation with acetic anhydride and acetate as the reagents, and a mixture of petroleum benzene and acetone with the ratio of 20:1 which is used as the TLC developer to trace the recomposition, a phase-transference benzyl ether protection, Baeyer-Villiger oxidation, one-step 2-,17-diacetoxylide hydrolysis -2-methylation, concentrated and hydrochloride acid 3- protection to product the intended product of 2-methoxyestradiol. The present invention has mild reaction condition, simple operation, the reagent which is easily accessible with low cost, thorough reaction, shortened reaction duration, simple post treatment, raised recovery rate and raised purity of the product, economized reagent and the decreased cost, as well as the prospect of industrialized production.

Description

technical field [0001] The invention belongs to the field of organic chemistry and medicine synthesis, and specifically relates to a synthesis method of compound 2-methoxyestradiol. Background technique [0002] Angiogenesis plays a key role in the process of tumor formation, invasion, and metastasis. Tumor tissues are richer in blood vessels than normal tissues, and blood vessels provide tumor tissues with nutrients and oxygen necessary for their growth. For ordinary adults, except for some special physiological needs, such as the female reproductive system, tissue damage or hypoxia, the endothelial cells of the vasculature are usually relatively quiescent, and these endothelial cells can survive for more than 1000 days in the body . Therefore, in the 1970s, Judah Folkman put forward the theory that tumor growth depends on new blood vessels, and proposed the idea of ​​inhibiting and eliminating tumors by inhibiting blood vessel growth and cutting off nutrient supply. [0...

Claims

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Application Information

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