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Ferulic acid derivative as well as preparation method and application thereof

A derivative, the technology of ferulic acid, applied in the field of pharmaceutical chemical synthesis, can solve the problems of low bioavailability, poor blood-brain barrier permeability, and clinical application limitations, and achieve high total yield, easy repeatability, and mild reaction conditions Effect

Pending Publication Date: 2022-06-07
XIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The clinical application of FA in the treatment of AD has been limited due to its poor blood-brain barrier (BBB) ​​permeability and low bioavailability

Method used

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  • Ferulic acid derivative as well as preparation method and application thereof
  • Ferulic acid derivative as well as preparation method and application thereof
  • Ferulic acid derivative as well as preparation method and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0017] The preparation method of a kind of ferulic acid derivative of the present invention is specifically implemented according to the following steps:

[0018] Step 1, using ferulic acid as a raw material, under the condition of concentrated sulfuric acid and methanol reflux reaction to prepare methyl ferulate;

[0019] The mass ratio of ferulic acid to methanol was 1:8; the reflux reaction temperature was 70°C, and the reflux reaction time was 3h;

[0020] Step 2, mix methyl ferulate with different substituted carbamoyl chlorides and add acetone K 2 CO 3 , carry out the reflux reaction, the reaction temperature is 60 ℃, and the reaction time is 7h; the ferulic acid carbamate substituted derivative is generated;

[0021] Different substituted carbamoyl chlorides are N-methyl-N-ethylformyl chloride, N,N-dimethylformyl chloride or N,N-diethylformyl chloride;

[0022] The mass ratio of methyl ferulate to carbamoyl chloride is 1:1.1;

[0023] In step 3, the ferulic acid car...

Embodiment 1

[0035] Synthesis of Example 1 Intermediate

[0036] a, (E)-3-(4-hydroxy-3-ethoxyphenyl) methyl acrylate (2)

[0037]

[0038] Add 3 g of ferulic acid (FA) (15.5 mmol) to a 100 mL eggplant-shaped flask, dissolve it in 30 mL of methanol, slowly add 1.2 mL (22.5 mmol) of concentrated sulfuric acid, and heat the system to 70 °C for 3 h. After the reaction was completed, the pH was adjusted to 7 with 10% NaOH after concentration under reduced pressure, extracted with ethyl acetate, washed with water, and the organic phase was washed with Na 2 SO 4 Then, concentrated under reduced pressure to obtain 3.1 g of yellow oil with a yield of 97%; it was identified as (E)-methyl 3-(4-hydroxy-3-ethoxyphenyl)acrylate.

[0039] Among them, the product is characterized as follows:

[0040] (E)-Methyl 3-(4-hydroxy-3-ethoxyphenyl)acrylate: 1 H-NMR (400MHz, CDCl 3 )δ7.64(1H,d,J=16.0Hz,H-7),7.08(1H,d,J=8.2Hz,H-5),7.04(1H,s,H-3),6.93(1H, d,J=8.0Hz,H-6),6.31(1H,d,J=16.0Hz,,H-8),6.07(1H,brs,O...

Embodiment 2

[0062] Example 2 Preparation of (E)-2-methoxy-4-(3-oxo-3-(phenylamino)-1-propenyl)phenyldimethylcarbamate (5a)

[0063]

[0064] First add compound (4a) 0.2mol, HATU (1.2eq), DIEPA (2eq), stir for 15min, add aniline (0.2mol), react at room temperature for 2h, spot plate detection after the reaction is completed, use petroleum ether: acetone (105: 30) Purify by column chromatography; white solid; yield 46.2%; identified as (E)-2-methoxy-4-(3-oxo-3-(phenylamino)-1-propenyl) Phenyldimethylcarbamate.

[0065] mp 178-180℃; 1 H-NMR (400MHz, CDCl 3)δ8.34(1H,s,H-9),7.65(2H,d,J=8.0Hz,H-11,15),7.47(1H,d,J=16Hz,H-7),7.32(2H ,t,H-12,14),7.09(1H,t,H-13),7.04(1H,d,J=8.0Hz,H-4),6.96(1H,d,J=8.0Hz,H- 3),6.89(1H,s,H-6),6.00(1H,d,J=16Hz,H-8),3.66(3H,s,OCH 3 ),3.19(3H,s,-CH 3 ),3.10(3H,s,-CH 3 ); ESI-MS m / z: 341.1[M+H] + .

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Abstract

The invention discloses a ferulic acid derivative as well as a preparation method and application thereof, specifically, ferulic acid is taken as a raw material, ferulic acid and methanol are subjected to reflux under the condition of concentrated sulfuric acid to obtain ferulic acid methyl ester, the ferulic acid methyl ester reacts with different substituted carbamoyl chloride to generate a ferulic acid carbamate substituted derivative, and the ferulic acid carbamate substituted derivative is obtained. Further removing a methyl protecting group under the action of lithium hydroxide to expose a carboxyl terminal, and finally reacting with different substituted aniline under the actions of HATU and DIPEA to generate the target ferulic acid derivative. In-vitro cholinesterase activity tests are carried out on the synthesized ferulic acid derivative, most of the compounds have inhibitory activity on cholinesterase, and the compound is an ideal cholinesterase-resistant chemical entity and has important significance in treatment of Alzheimer's disease.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical synthesis, in particular to a ferulic acid derivative, and also to a preparation method and application of the ferulic acid derivative. Background technique [0002] my country has entered an aging society, and the health of the elderly has received much attention. Alzheimer's disease (AD), as the most common type of senile dementia, has no specific drug at present, so the research on AD has become a hot issue of many scientific researches. Although there are various theories about its pathogenesis, it may be related to gene mutation, β-amyloid (Aβ) deposition, damage to the central cholinergic system, toxicity of excitatory amino acids, inflammatory response and immune system impairment, Oxidative stress and calcium homeostasis disorders are related, but its therapeutic drugs are still mainly acetylcholinesterase inhibitors (ACEI). Therefore, finding new anti-AD drugs from natural pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/44C07C269/06A61P25/28
CPCC07C271/44A61P25/28Y02A50/30
Inventor 关丽劳可静陈云梅胡娅琪王春阳赵惠茹李伟泽宋旭超
Owner XIAN MEDICAL UNIV
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