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Gem-difluoro ethyl substitutional diphenylethene and diphenylethane derivative as well as preparation method and application thereof

A technology of stilbene and difluoroethyl, applied in the field of drug synthesis to achieve the effect of enhancing in vitro anti-tumor activity and strengthening in vitro anti-tumor activity

Active Publication Date: 2017-11-03
SHANGHAI ECUST BIOMEDICINE CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The previously studied CA-4 fluorine-containing compounds are mostly substituted by monofluorine and trifluoromethyl, and there are no reports on diphenylethylene and diphenylethane derivatives substituted by gem-difluoroethyl

Method used

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  • Gem-difluoro ethyl substitutional diphenylethene and diphenylethane derivative as well as preparation method and application thereof
  • Gem-difluoro ethyl substitutional diphenylethene and diphenylethane derivative as well as preparation method and application thereof
  • Gem-difluoro ethyl substitutional diphenylethene and diphenylethane derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 Synthesis of 4-(1,1-difluoro)ethylbenzaldehyde

[0023]

[0024] Step 1: Preparation of methyl 4-(1,1-difluoroethyl)benzoate

[0025] Dissolve methyl 4-acetylbenzoate (5.00 g, 28.06 mmol) in 40 mL of anhydrous CH 2 Cl 2 Add to sealed tube, N 2 Protection, slowly add DAST (diethylaminosulfur trifluoride) (12mL, 3.4eq) dropwise at -40°C, and then heat in an oil bath at 60°C for 24h, after the reaction is completed, it will drop below 0°C, and use saturated NaHCO 3 Aqueous solution quenches the reaction, CH 2 Cl 2 Extract, combine the organic phases, concentrate, and separate by column chromatography with EA:PE=1:150 to obtain 3.30 g of white solid with a yield of 59%. Mp:35.2-35.7℃. 1 H NMR (CDCl 3,500MHz): δ1.92(t,3H,J=18.0Hz),3.93(s,3H),7.57(d,2H,J=8.0Hz),8.09(d,2H,J=8.0Hz). 13 C NMR (CDCl 3 ,125MHz): δ166.3,142.6142.4,142.2,131.4,129.8,124.7,123.8,121.4,119.5,52.27,26.1,25.9,25.6. 19 F NMR (CDCl 3 ,470MHz):δ-88.70.MS(m / z):200(M + ).ESI-HRMS(m / z...

Embodiment 2

[0030] Preparation of Example 2 (Z / E)-3,4,5-trimethoxy-4'-(1,1-difluoroethyl)stilbene

[0031]

[0032] N 2 Under protection, 3,4,5-trimethoxybenzyl bromidetriphenylphosphine bromide (3.08g, 5.88mmol) was suspended in 50mL of anhydrous THF solution, and n-butyllithium (4.5 mL, 7.06mmol, 1.2eq), then reacted for 1h, then slowly added dropwise a THF solution (5mL) of 4-(1,1-difluoroethyl)benzaldehyde (1.00g, 5.88mmol) to the reaction system, liter Reaction at room temperature overnight for 12h. After the reaction, cool the system to below -5°C, add saturated NaCl aqueous solution, extract with EA, combine the organic phases, anhydrous NaCl 2 SO 4 After drying, filtering and concentrating, column chromatography separated EA:PE=1:25 to obtain 1.20 g of oil as a cis-trans mixture with a yield of 64% (Z:E=4:1). Further separation by column chromatography yielded pure cis-trans isomers.

[0033] (Z)-3,4,5-Trimethoxy-4'-(1,1-difluoroethyl)stilbene

[0034] White oil Z-isomer:...

Embodiment 3

[0037] Example 3 Preparation of 3,4,5-trimethoxy-4'-(1,1-difluoroethyl)diphenylethane

[0038]

[0039] Dissolve (Z / E)-3,4,5-trimethoxy-4'-(1,1-difluoroethyl)stilbene (1.20 g, 3.6 mmol) in 30 mL of ethanol and add Pd / C (0.10g, 0.9mmol), H 2 The excess was stirred overnight at room temperature. After the reaction, the Pd / C was removed by filtration, and the solvent was spin-dried to obtain 1.10 g of a white solid with a yield of 90%. Mp:60.1-60.7℃. 1 H NMR (CDCl 3 ,500MHz):δ1.91(t,3H,J=18.0Hz),2.86(m,2H),2.94(m,2H),3.82(d,9H,J=10.0Hz),6.34(s,2H) ,7.22(d,2H,J=7.5Hz),7.42(d,2H,J=7.5Hz). 13 C NMR (CDCl 3 ,125MHz): δ153.1,143.3,137.1,136.3,136.2,135.9,135.7,128.6,124.7,124.6,124.6,123.8,121.9,120.0,105.5,60.9,56.1,38.1,37.7,29,125.25. 19 F NMR (CDCl 3 ,470MHz):δ-86.84.MS(m / z):336(M + ).ESI-HRMS(m / z): calculated for C 19 h 22 f 2 o 3(M+H) + :337.1615,found:337.1610.

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Abstract

The invention discloses gem-difluoro ethyl substitutional diphenylethene and diphenylethene diphenylethane derivatives as well as a preparation method and application thereof. A 4' bit of a B aromatic ring of diphenylethane / diphenylethene is subjected to chemical structure modification through gem-difluoro ethyl, and meanwhile, a 2' bit is modified into nitro or an amino group and other substituent groups; the gem-difluoro ethyl substitutional diphenylethene and diphenylethane derivative has relatively high antitumor activity in vitro, and the antitumor activity of a trans-form is better than the antitumor activity of a cis-form; with the introduction of fluorine atoms, not only is the physical property of the compound changed, but also the antitumor activity in vitro is improved at the same time, and the derivative has a relatively good inhibiting effect on multiple tumor cells.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a gem-difluoroethyl-substituted diphenylethylene and diphenylethane derivatives and a preparation method and application thereof. Background technique [0002] Combretastatin A-4 (CA-4) is a stilbene compound isolated from the South African shrub willow bark combretum caffrum by Pettit et al. It can specifically recognize and destroy tumor blood vessels, so that tumor cells do not get enough "Starved to death" of nutrients. By acting on the colchicine-binding site, CA-4 can inhibit tubulin polymerization and thereby prevent tumor blood flow. However, CA-4 and its derivatives still have many defects, such as poor water solubility, unstable cis structure, and inactive trans structure, which greatly hinder their clinical trials. Therefore, a lot of research work has been done around the structural modification of CA-4 analogues for a long time. In most cases, when modifyin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C41/30C07C43/225C07C201/12C07C205/35C07C213/02C07C217/80C07C231/02C07C237/04A61K31/09A61K31/136A61K31/167A61P35/00
CPCC07C43/225C07C205/35C07C217/80C07C237/04
Inventor 吴范宏马仲林开振鹏黄磊磊李丹丹黄金文
Owner SHANGHAI ECUST BIOMEDICINE CO LTD
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