3,4-diarylmaleimide derivative and preparation method as well as application thereof

A technology of maleimide and derivatives, applied in the field of 3,4-diarylmaleimide derivatives and its preparation, can solve problems such as ineffective reversal of atherosclerosis and safety risks

Active Publication Date: 2015-03-25
南京易腾药物研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ezetimibe is currently the only cholesterol absorption inhibitor on the market, but it cannot effectively reverse atherosclerosis and has potential safety risks. There...

Method used

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  • 3,4-diarylmaleimide derivative and preparation method as well as application thereof
  • 3,4-diarylmaleimide derivative and preparation method as well as application thereof
  • 3,4-diarylmaleimide derivative and preparation method as well as application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: Preparation of α-bromo-p-fluoroacetophenone.

[0067] Dissolve 10g (72.4mmol) of p-fluoroacetophenone in 100mL of acetonitrile, and add 11.57g (72.4mmol) of Br dropwise under stirring 2 acetonitrile solution, stirred overnight (8-10h), after the reaction is complete, remove the solvent by rotary evaporation under reduced pressure, redissolve in ethyl acetate, wash with brine three times, dry over anhydrous sodium sulfate, filter, remove the solvent by rotary evaporation under reduced pressure, and use 50mL Add a few drops of diethyl ether to cyclohexane to make a slurry and filter to obtain 14.2 g of white crystals, with a yield of 90.8%.

[0068] 1 H NMR (300M, CDCl 3 ):δ=4.41(s,2H,-CH 2 -), 7.17(d, J=8.4Hz, 2H, Ar-H), 8.03(dd, J=5.4, 8.7Hz, 2H, Ar-H);

[0069] MS(EI,m / z):[M - ] 215.0.

Embodiment 2

[0070] Example 2: Preparation of α-bromo-p-methoxyacetophenone.

[0071] 12.80g (85.24mmol) of p-methoxyacetophenone was dissolved in 150mL of acetonitrile, and 13.62g (85.24mmol) of Br 2 acetonitrile solution, stirred overnight (8-10h), after the reaction is complete, remove the solvent by rotary evaporation under reduced pressure, redissolve in ethyl acetate, wash with brine three times, dry over anhydrous sodium sulfate, filter, remove the solvent by rotary evaporation under reduced pressure, and use 50mL Add a few drops of diethyl ether to cyclohexane to make a slurry and filter to obtain 14.31 g of white crystals, yield: 73.5%.

[0072] 1 H NMR (500M, CDCl 3 ):δ=3.89(s,3H,-OCH 3 ),4.40(s,2H,-CH 2 -), 6.96(d, J=8.5Hz, 2H, Ar-H), 7.97(d, J=9Hz, 2H, Ar-H);

[0073] MS(EI,m / z):[M - ] 226.9.

Embodiment 3

[0074] Example 3: Preparation of 2-azido-(4-fluorophenyl)ethanone.

[0075]Dissolve 13.09g (60mmol) of α-bromo-p-fluoroacetophenone in 80mL of methanol, cool down to 0°C, and add 4.71g (72mmol) of NaN 3 Aqueous solution, reaction 4h. After the reaction was complete, 200 mL of water was added under ice-bath conditions, and a white solid precipitated out. The product was obtained by direct filtration, and dried to obtain 10.6 g of product, yield: 98%.

[0076] 1 H NMR (300M, CDCl 3 ):δ=4.52(s,2H,-CH 2 -), 7.18(d, J=8.4Hz, 2H, Ar-H), 7.95(dd, J=5.4, 8.7Hz, 2H, Ar-H);

[0077] MS(EI,m / z):[M + ] 179.0.

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Abstract

The invention discloses a 3,4-diarylmaleimide derivative and a preparation method as well as application thereof. The general formula of the 3,4-diarylmaleimide derivative is shown in the specification. The 3,4-diarylmaleimide derivative can be applied to treating or preventing atherosclerosis or reducing plasma cholesterol level, has higher plasma cholesterol reduction activity and has broader market prospect.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and specifically relates to 3,4-diarylmaleimide derivatives and their preparation methods and applications. Background technique [0002] Cardiovascular and cerebrovascular diseases are the number one killer that endangers human life and health today. Hyperlipidemia caused by blood lipid metabolism disorders is one of the important causes of cardiovascular and cerebrovascular diseases such as atherosclerosis, liver cirrhosis, and hypertension. Currently clinically used cholesterol-lowering drugs mainly include statins, fibrates, niacin derivatives and bile acid sequestrants, but the side effects of these drugs are also obvious, especially cerivastatin among statins Many clinical deaths were caused by side effects of rhabdomyolysis. (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)- 2-azetidinone (Ezetimibe, Ezetimibe, Zetia TM ) is a new type...

Claims

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Application Information

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IPC IPC(8): C07D207/444C07D409/12A61K31/4015A61K31/4025A61P3/06
CPCC07D207/444C07D409/12
Inventor 王玉斌秦慧陆鹏袁新睿
Owner 南京易腾药物研究院有限公司
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