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Salicylamide ether compounds of pleuromutilin and preparation method thereof

A technology of pleuromutilin and salicylamide ether, which is applied in the field of chemical synthesis of drugs, can solve the problems of adverse reactions and low bioavailability, and achieve the effect of improving drug efficacy and reducing costs

Inactive Publication Date: 2011-09-14
WUHAN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, with the increasing drug resistance of G+ bacteria, including methicillin-resistant Staphylococcus aureus, penicillin-resistant pneumococcus, and vancomycin-resistant enterococcus, the commonly used antibacterial drugs linezolid, quinupristine / Although dalfopristin and teicopridine have certain curative effects on infections caused by drug-resistant bacteria, their wide application is limited due to serious adverse reactions and low bioavailability.

Method used

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  • Salicylamide ether compounds of pleuromutilin and preparation method thereof
  • Salicylamide ether compounds of pleuromutilin and preparation method thereof
  • Salicylamide ether compounds of pleuromutilin and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 (when m=2 in the target compound I):

[0032]

[0033] Synthesis of Intermediate Pleuromutilin Methanesulfonate (II)

[0034] Step 1: put pleuromutilin (37.85 grams, 0.1 mole) into a 250ml there-necked flask, add 120ml of dichloromethane as a solvent, first add triethylamine (12.144 grams, 0.12 mole) and stir for 1 hour at room temperature, then Methanesulfonyl chloride (14.31 g, 0.125 mol) was slowly added dropwise to the reaction mixture in an ice-salt bath. After the dropwise addition, the mixture was stirred and reacted in an ice-salt bath for 30 minutes. Excessive triethylamine and methanesulfonyl chloride in the reaction solution can be washed away to obtain intermediate II;

[0035] Synthesis of Intermediate Methyl Salicylate (III)

[0036] Step 2: Add salicylic acid (20.7 grams, 0.15 moles) and methanol (24 grams, 0.75 moles) in a 100ml there-necked flask, add an appropriate amount of catalyst concentrated sulfuric acid at 60-65 ° C and stir for r...

Embodiment 2

[0040] Embodiment 2 (m=2 in the order compound I):

[0041] Synthesis of the Intermediate Pleuromutilin Methanesulfonate (II)

[0042] Step 1: put pleuromutilin (5.67 grams, 0.015 moles) into a 100ml there-necked flask, add 30ml of dichloromethane as a solvent, first add triethylamine (7.59 grams, 0.075 moles) and stir for 1 hour at room temperature, then Methanesulfonyl chloride (8.59 g, 0.075 mol) was added dropwise to the reaction mixture in an ice-salt bath, and after the dropwise addition was completed, the stirring reaction was continued for 30 minutes, and the excess Tris Ethylamine and methanesulfonyl chloride are washed away to give intermediate II.

[0043] Synthesis of Intermediate Methyl Salicylate (III)

[0044] Step 2: Add salicylic acid (2.07 grams, 0.015 moles) and methanol (7.2 grams, 0.225 moles) in a 100ml three-necked flask, add an appropriate amount of catalyst concentrated sulfuric acid at 60-65 ° C and stir for reflux reaction for 8 hours, wherein the ...

Embodiment 3

[0048] Embodiment 3 (m=3 among the order compound I):

[0049]

[0050] Synthesis of the Intermediate Pleuromutilin Methanesulfonate (II)

[0051] Step 1: put pleuromutilin (37.85 grams, 0.1 mole) into a 250ml there-necked flask, add 120ml of dichloromethane as a solvent, first add triethylamine (12.144 grams, 0.12 mole) and stir for 1 hour at room temperature, then Methanesulfonyl chloride (14.31 g, 0.125 mol) was slowly added dropwise to the reaction mixture in an ice-salt bath. After the dropwise addition, the stirring reaction was continued for 30 minutes. Triethylamine and methanesulfonyl chloride can be washed away to obtain intermediate II;

[0052] Synthesis of Intermediate Methyl Salicylate (III)

[0053] Step 2: Add salicylic acid (20.7 grams, 0.15 moles) and methanol (24 grams, 0.75 moles) in a 100ml there-necked flask, add an appropriate amount of catalyst concentrated sulfuric acid at 60-65 ° C and stir for reflux reaction for 24 hours, wherein the solvent is...

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Abstract

The invention relates to pleuromutilin derivatives, particularly salicylamide ether compounds of pleuromutilin and a preparation method thereof. The structural formula of the salicylamide ether compounds of pleuromutilin is disclosed as a general formula I, wherein R is NHCmH2mCH3, and m is a whole number which is greater than or equal to 0. In the invention, the pleuromutilin, which is used as the raw material, is esterified, subjected to amine-ester exchange and etherified to obtain the pleuromutilin derivatives. The related pharmaceutic adjuvant groups are changed to enhance the pharmaceutic activity, thereby achieving the corresponding pharmacodynamic goal. In normal cases, most receptors are proteins or derivatives thereof; the amido group contained in the pharmaceutic molecule can promote the pharmaceutic molecule to be combined with the corresponding receptor in an easier way, thereby enhancing the pharmaceutic effect. All the pharmaceutic materials in the synthetic process are common, cheap and accessible, thereby lowering the production cost.

Description

technical field [0001] The invention relates to the field of chemically synthesized medicines, in particular to a pleuromutilin derivative salicylamide ether compound of pleuromutilin and a preparation method thereof. Background technique [0002] Pleuromutilin was first isolated and initially identified by Kavanagh et al. in 1951. It is a class of broad-spectrum diterpene antibiotics produced by the higher fungi Pleuromyces and Pleuromyces, which can effectively inhibit Gram Positive bacteria, especially staphylococcus and streptococcus are the most obvious, and also have therapeutic effect on mycoplasma infection. Many of its derivatives have stronger antibacterial activity and scope than pleuromutilin, and have a wider antibacterial spectrum. In recent years, with the increasing drug resistance of G+ bacteria, including methicillin-resistant Staphylococcus aureus, penicillin-resistant pneumococcus, and vancomycin-resistant enterococcus, the commonly used antibacterial dru...

Claims

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Application Information

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IPC IPC(8): C07C235/60C07C231/12A61P31/04
Inventor 祝宏潘志权陈嵘唐志焱荣凯峰
Owner WUHAN INSTITUTE OF TECHNOLOGY
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