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3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof

A technology of methoxybenzamide and hydroxybenzamide, which is applied in the field of 3-methoxybenzamide derivatives and its preparation and application, and can solve the problems of low antibacterial activity and poor druggability

Inactive Publication Date: 2012-07-04
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In view of the above-mentioned prior art, aiming at the problems of low antibacterial activity and poor druggability of the current 3-MBA derivatives, and explore possible hydrogen bonding sites and C-3 side chains on the C-3 position of 3-MBA The optimal length, the subject group of the present invention has designed and synthesized a series of novel compounds-3-methoxybenzamide derivatives with good expected activity by means of computer-aided drug design (CADD), and the present invention also provides its preparation method

Method used

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  • 3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof
  • 3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof
  • 3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof

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Embodiment 1

[0064] The preparation of embodiment 1 3-hydroxybenzamide

[0065] 3-Hydroxybenzoic acid (10 g, 72.4 mmol, 1.0 eq) was suspended in toluene (60 ml), and thionyl chloride (7.8 ml, 108.6 mmol, 1.5 eq) was slowly added at room temperature. The solution was heated to reflux for 4.5 hours. Afterwards, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (27ml), cooled to -5°C, and saturated concentrated ammonia solution (28ml) was slowly added dropwise, the reaction mixture was slowly raised to room temperature, and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the resulting solid was suspended in water and filtered. The collected solid was washed three times with purified water (about 20 ml), and then dried in vacuo to give 3-hydroxybenzamide (6.94 g, 70.0%) as an off-white solid, melting point 165-167 ° C, R f =0.12 (the developing solvent is petroleum ether / ethyl ace...

Embodiment 2

[0066] Example 2 General method for alkylation of 3-hydroxybenzamide with alkyl bromide

[0067] a) K 2 CO 3 (2.07g, 15mmol, 1.5eq) was added to a suspension of 3-hydroxybenzamide (1.37g, 10mmol, 1.0eq) in DMF (110ml). The mixture was stirred at room temperature for about 15 minutes, then 1,2-dibromoethane (7.51 g, 40 mmol, 4 equiv) was added. The resulting mixture was stirred at 60°C for 16 hours. Afterwards, the reaction was cooled to room temperature, any undissolved solids were filtered off and the filtrate was evaporated to dryness under reduced pressure. The evaporated residue was dissolved in ethyl acetate and washed successively with K 2 CO 3 solution (the purpose is to remove incompletely reacted 3-hydroxybenzamide), and saturated sodium chloride solution for washing. with MgSO 4 The organic layer was dried and evaporated to a small volume under reduced pressure. The evaporated solid was separated and purified on a silica gel column to obtain the desired compo...

Embodiment 3

[0072] Example 3 General Method for Alkylation of 3-Hydroxybenzamides with Alkyl Chlorides

[0073] a) Dissolve 3-hydroxybenzamide (1.37g, 10mmol, 1.0 equivalent) in DMF (25ml), add K 2 CO 3 (2.48g, 18mmol, 1.8eq) and NaI (0.45g, 3mmol, 0.3eq). The above suspension was stirred for about 5 minutes and 1,3-dichloropropane (4.52 g, 40 mmol, 4 equiv) was added. The resulting mixture was slowly heated to 60°C, kept for 18 hours, and the heating was stopped. The reaction was cooled to room temperature, any undissolved solids were filtered off and the filtrate was evaporated to dryness under reduced pressure. The evaporated residue was dissolved in ethyl acetate and washed successively with K 2 CO 3 solution and saturated sodium chloride solution. with MgSO 4 The organic layer was dried and evaporated to a small volume under reduced pressure. The evaporated solid was separated and purified on a silica gel column to obtain the desired compound (target compound 6) (1.22 g, 56.9...

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Abstract

The invention discloses a 3-methoxybenzamide (MBA) derivant, which is disclosed in the following structural formula (1), wherein R1 is chlorine or bromine, R2 and R3 are independently fluorine or hydrogen, and n is an integer of 1-5. According to the 3-MBA derivant, a hydrophobic halogenated hydrocarbon side chain of which the length is 3-7 atoms is introduced on the C-3 site of 3-MBA to discover the optimal length of the hydrocarbon side chain introduced on C-3 of the 3-MBA. Meanwhile, a chlorine atom and a bromine atom with better lipid solubility are introduced into the tail end of the side chain so as to enhance the antibacterial activity of the derivant. In order to improve the target and the antibacterial activity of a compound, fluorine atoms are introduced onto the C-2 site and the C-6 site of the 3-MBA. The experiment proves that the compound disclosed by the invention can be used for specifically inhibiting the activity of various pathogenic bacteria even drug resistant bacteria, such as staphylococcus aureus, staphylococcus epidermidis, staphylococcus haemolyticus, staphylococcus saprophyticus, bacillus subtilis, bacillus anthracis and the like.

Description

technical field [0001] The invention relates to a 3-methoxybenzamide derivative, a preparation method and application thereof. Background technique [0002] At present, humans have developed various types of antibacterial drugs, and the most widely used ones are penicillins, cephalosporins, tetracyclines, aminoglycosides, macrolides, chloramphenicols, quinolones, trimethoprim and chlorine. Mycin etc. The mechanisms of action of the above antibacterial agents vary. Throughout the 20th century, antibacterial drugs played a vital role in the survival and development of human beings. [0003] However, in recent years, with the widespread clinical application of antimicrobial agents, especially the abuse, and the lack of correct guidance, bacterial drug resistance has increased year by year. In recent years, a variety of drug-resistant bacteria have emerged, and they have developed resistance to commonly used antibiotics in clinical practice. The more common drug-resistant ba...

Claims

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Application Information

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IPC IPC(8): C07C235/46C07C231/12A61K31/166A61P31/04
Inventor 马淑涛齐昀坤马思提李新闫蜜
Owner SHANDONG UNIV
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