Preparation method of rifamycin-nitroiminazole coupled molecule

A technology of nitroimidazole coupling and rifamycin is applied in the field of preparation of rifamycin-nitroimidazole coupling molecules, which can solve the problems of low product yield and the like, and achieve the effect of improving product yield

Active Publication Date: 2015-11-11
TENNOR THERAPEUTICS (SUZHOU) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Because the disadvantage of the above preparation method is that not only the reaction conditions must be controlled at low temperature, but also the yield of the final product is low, so it is very important to study the preparation method with normal temperature and high yield.

Method used

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  • Preparation method of rifamycin-nitroiminazole coupled molecule
  • Preparation method of rifamycin-nitroiminazole coupled molecule
  • Preparation method of rifamycin-nitroiminazole coupled molecule

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1 A kind of preparation method of rifamycin-nitroimidazole coupling molecule

[0026] Step 1: Synthesis of 2-(2-methyl-5-nitro-1hydro-imidazol-1-yl)ethyl methanesulfonate

[0027]

[0028] Add dry dichloromethane (500mL) into a 1L three-necked flask, add metronidazole (98.6g, 0.576mol), then add 4-dimethylaminopyridine (3.5g, 0.03mol) and triethylamine (120mL) . After cooling down to 0°C, methanesulfonyl chloride (54 mL, 0.692 mol) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction was slowly raised to room temperature and stirred overnight. After the reaction was complete, the solid was filtered out, and the solid was dried in vacuo to further remove residual solvent. The resulting crude product was added to 500 mL of water, stirred, filtered, and the filter cake was vacuum-dried to obtain 2-(2-methyl-5-nitro-1 hydrogen-imidazol-1-yl) ethyl methanesulfonate (139 g , yield 97.5%). Mass Spectrum (ESI, M+1): The...

Embodiment 2

[0038] Embodiment 2 A kind of preparation method of rifamycin-nitroimidazole coupling molecule

[0039] Step 1: Synthesis of 2-(2-methyl-5-nitro-1hydro-imidazol-1-yl)ethyl trifluoromethylsulfonate

[0040]

[0041] Add dry dichloromethane (500mL) into a 1L three-necked flask, add metronidazole (98.6g, 0.576mol), then add 4-dimethylaminopyridine (3.5g, 0.03mol) and triethylamine (120mL) . After cooling to -10°C, trifluoromethanesulfonic anhydride (195 g, 0.692 mol) was slowly added dropwise. After the dropwise addition, the temperature was slowly raised to room temperature and stirred overnight. After the reaction was complete, the solid was filtered out, and the filter cake was vacuum-dried. The resulting crude product was added to 500 mL of water, stirred, filtered, and the filter cake was vacuum-dried to obtain 2-(2-methyl-5-nitro-1 hydrogen-imidazol-1-yl)ethyl trifluoromethylsulfonium Ester (173 g, yield 99.1%). Mass Spectrum (ESI, M+1): theoretical 304.0, found 304....

Embodiment 3

[0050] Embodiment 3 A kind of preparation method of rifamycin-nitroimidazole coupling molecule

[0051] Step 1: Synthesis of 2-(2-methyl-5-nitro-1hydro-imidazol-1-yl)ethyl p-toluenesulfonate

[0052]

[0053] Add dry dichloromethane (500mL) into a 1L three-necked flask, add metronidazole (98.6g, 0.576mol), then add 4-dimethylaminopyridine (3.5g, 0.03mol) and triethylamine (120mL) . After cooling to 10°C, p-toluenesulfonyl chloride (132 g, 0.692 mol) was slowly added dropwise to the reaction liquid. After the dropwise addition, the temperature was slowly raised to room temperature, and stirred overnight. After the reaction was complete, the solid was filtered out, and the filter cake was vacuum-dried. The obtained crude product was added into 500 mL of water, stirred, filtered, and the filter cake was vacuum-dried to obtain the title compound (158.3 g, yield 84.5%). Mass spectrum (ESI, M+1): theoretical 326.1, found 326.1.

[0054] Step 2: Synthesis of 9-(2-(2-methyl-5-ni...

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Abstract

The invention discloses a preparation method of a rifamycin-nitroiminazole coupled molecule. By using metronidazole as the raw material and changing the synthesis route, the preparation method overcomes the defect that the reaction condition must be controlled at low temperature, and enhances the yield of the target product.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a preparation method of a rifamycin-nitroimidazole coupling molecule. Background technique [0002] Rifamycin is a class of antibiotics produced by Streptococcus mediterranei. It has a broad-spectrum antibacterial effect against Gram-positive bacteria such as Mycobacterium tuberculosis, Leprosy, Streptococcus, and pneumococcus, especially drug-resistant Staphylococcus aureus. Bacteria are very powerful. [0003] A rifamycin-nitroimidazole conjugate molecule is a derivative of rifamycin, named 4-deoxy-3,4-[2-spirocycle-[1-[2-(2-methyl- 5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1hydrogen)-imidazo-(2,5-dihydro)rifamycin S, its structural formula is as follows I: [0004] [0005] U.S. Patent No. 7,678,791B2 reports the method for preparing the above-mentioned compound, and the synthetic route is as follows: [0006] [0007] Since the disadvantage of the ab...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/22
CPCC07D498/22
Inventor 马振坤张天元丁俊
Owner TENNOR THERAPEUTICS (SUZHOU) LTD
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