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Fluoro-substitution diphenylethane derivative and preparation method and application thereof

A technology of diphenylethane and derivatives, which is applied in the field of drug synthesis, can solve the problems of many by-products, tumor cell apoptosis, harsh reaction conditions, etc., and achieve the effect of inhibition, obvious effect, and strong anti-tumor activity in vitro

Active Publication Date: 2019-12-03
SHANGHAI INST OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, it has been reported in the literature that the anti-tumor effect of erianin may also be related to the induction of tumor cell apoptosis by acting on telomerase.
[0003] There have been many reports on stilbene fluorine-substituted modifiers, most of which are monofluoro-substituted and trifluoromethyl-substituted, but there are no reports on derivatives substituted by bridging fluorine, and the synthesis theory of derivatives substituted by bridging fluorine is more complex. Large, the current synthesis steps of bridge fluorine-substituted derivatives are relatively complicated, the requirements are harsh, and there are many by-products. The current synthesis method is not suitable for large-scale production, and the synthesis conditions need to be further optimized.
However, the above technical scheme requires anhydrous and oxygen-free conditions during the experimental operation, the reaction conditions are harsh, there is no stereoselectivity, and the yield is low

Method used

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  • Fluoro-substitution diphenylethane derivative and preparation method and application thereof
  • Fluoro-substitution diphenylethane derivative and preparation method and application thereof
  • Fluoro-substitution diphenylethane derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Synthesis of (E)-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)acrylic acid.

[0044]3,4,5-trimethoxyphenylacetic acid (9.1g, 40mmol) and p-methoxybenzaldehyde (2a, 5.5g, 40mmol) were dissolved in 150mL of acetic anhydride, and triethylamine (8.1g, 80mmol), the mixture was heated at 110°C for 6h. After cooling, it was acidified with concentrated hydrochloric acid, poured into ice water, and stirred for 4 hours to obtain a light yellow solid, which was filtered, dissolved in 10% NaOH aqueous solution, washed with ethyl acetate to decolorize, the organic layer was separated, and the aqueous phase was retained. Hydrochloric acid was added to the aqueous phase until pH = 3-4. The precipitated solid was filtered and recrystallized from ethyl acetate to obtain 3a, 10.8g, yield 78.6%, white solid, mp: 185.6-186.0°C.

[0045] 1 H NMR (500MHz, CDCl 3 )δ7.88(s,1H),7.05(d,J=10.0Hz,2H),6.72(d,J=5.0Hz,2H),6.46(s,2H),3.89(s,3H),3.77( s,9H);

[0046] 13 C NMR (125MHz, CDCl 3 )...

Embodiment 2

[0067] Preparation of 5-(1,1-difluoro-2-(4-methoxyphenyl)ethyl)-1,2,3-trimethoxybenzene (6a)

[0068] It is one of the fluorine-substituted diphenylethane derivatives.

[0069] Put 5a (5mmol), DAST (15mL) and ethylene glycol dimethyl ether (5mL) into a pressure-resistant glass-sealed tube reactor, seal it, heat to 80°C, and stir for 24h. Cool to room temperature, open the bottle cap, pour the reaction solution into ice water, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, spin to dryness and concentrate, and purify by column chromatography to obtain 6a (0.7g, yield 43.2%), yellow oil.

[0070] 1 H NMR (500MHz, CDCl 3 )δ7.02(d, J=10.0Hz, 2H), 6.79(d, J=5.0Hz, 2H), 6.47(s, 2H), 3.84(s, 3H), 3.77(s, 9H), 3.31( t, J HF =15.5Hz,2H); 19 F NMR (470MHz, CDCl 3 )δ-94.42(s);

[0071] 13 C NMR (125MHz, CDCl 3 )δ158.96, 152.94(x2), 138.93, 132.25(t, J CF = 25.63Hz), 131.66(x2), 124.78(t, J CF=10Hz), 121.92(t, J CF =242.5Hz),...

Embodiment 3

[0074] Preparation of 5-(2,2-difluoro-2-(3,4,5-trimethoxyphenyl)ethyl)-2-methoxyphenol (6d).

[0075] It is one of the fluorine-substituted diphenylethane derivatives.

[0076] Put 5c (5mmol), DAST (15mL) and ethylene glycol dimethyl ether (5mL) into a pressure-resistant glass-sealed tube reactor, seal it, heat to 80°C, and stir for 24h. After cooling to room temperature, the reaction solution was poured into ice water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by spinning to dryness, and purified by column chromatography to obtain 6c, a yellow oil. used directly in the next step.

[0077] Dissolve 6c in ethanol, add 10% palladium on carbon, and hydrogenate at normal pressure to obtain 6d (0.7g, two-step yield 40.1%), white solid, mp:98.3-98.9℃.

[0078] 1 H NMR (500MHz, CDCl 3 )δ6.85-6.71(m,2H),6.56-6.36(m,3H),5.61(s,1H), 3.84(s,3H),3.79-3.75(m,9H),3.29(t,J HF =17.5,2H);

[0079] 19 F NMR...

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Abstract

The invention relates to a fluoro-substitution diphenylethane derivative. The fluoro-substitution diphenylethane derivative is characterized in that the structure of the fluoro-substitution diphenylethane derivative is shown as the general formula (I) (please see the specifications for the general formula (I)), wherein in the general formula (I), R1 is methyl or ethyl, R2 is hydrogen or fluorine,and R is hydrogen, oxhydryl, benzyloxy, phosphate ester or phosphate. Compared with the prior art, fluorine-substituting modification is conducted on a bridged bond of diphenylethane, the obtained fluoro-diphenylethane derivative has high in-vitro anti-tumor activity, physical, chemical and biological properties of a compound are changed because of introduction of a fluorine atom, and the obviousinhibition effect on tumor cells is achieved.

Description

technical field [0001] The present invention relates to the technical field of drug synthesis, in particular to a fluorine-substituted diphenylethane derivative, its preparation method and application. Background technique [0002] Erianin, whose chemical name is 3,4,5-trimethoxy-3'-hydroxy-4'-methoxydiphenylethane (code name: MLS), is a natural compound extracted from the precious Chinese herbal medicine Dendrobium Diphenylethane active ingredients have anti-tumor effect. Erianin has the same structural features as the stilbene natural product Combretastatin A-4 (code name CA4, also known as windmill) in structure, and has a common AB ring structure. Erianin is equivalent to the vinyl bridge being hydrogenated the CA4. Like CA4, Erianin is also a tubulin inhibitor and has a strong tumor blood vessel targeting destruction effect, acting on the colchicine binding site. In addition, it has been reported in the literature that the antitumor effect of erianin may also be rela...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C43/225C07C41/22C07C43/23C07C41/26C07F9/12C07C59/64C07C51/347C07C271/16C07C269/00C07C49/84C07C45/00A61K31/09A61K31/661A61P35/00A61P35/02A61P19/02A61P27/06A61P31/04A61P31/10A61P31/22A61P27/02A61P17/06A61P31/18A61P15/00
CPCA61K31/09A61K31/661A61P15/00A61P17/06A61P19/02A61P27/02A61P27/06A61P31/04A61P31/10A61P31/18A61P31/22A61P35/00A61P35/02C07C41/22C07C41/26C07C43/225C07C43/23C07C45/00C07C51/347C07C269/00C07F9/12C07C59/64C07C271/16C07C49/84
Inventor 黄金文李英姿黄磊磊李玉洁吴范宏舒海英
Owner SHANGHAI INST OF TECH
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