Method and technology for synthesizing and producing antibiotic medicament namely 1-(o-fluorophenyl) dihydropyridone

A synthesis method and technology of production process are applied in the field of synthesis, production and process of antibiotic drug 1-(o-fluorophenyl)dihydropyridone, which can solve the problem of insufficient antibacterial activity, achieve low bone marrow suppression, Strong antibacterial activity, low monoamine oxidase inhibitory effect

Active Publication Date: 2010-08-11
SHANGHAI MICURX LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this representative drug of oxazolidinones can be used for the treatment of microbial infections, its antibacterial activity is still not high enough and serious side effects limit its application; wherein, such as Zyvox R Monoamine oxidase inhibition, myelosuppression, and myelotoxicity are the main factors limiting the use of linezolid, as noted in the "Cautions" section of the labeling

Method used

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  • Method and technology for synthesizing and producing antibiotic medicament namely 1-(o-fluorophenyl) dihydropyridone
  • Method and technology for synthesizing and producing antibiotic medicament namely 1-(o-fluorophenyl) dihydropyridone
  • Method and technology for synthesizing and producing antibiotic medicament namely 1-(o-fluorophenyl) dihydropyridone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160] Example 1. Compound structure

[0161]

[0162] Compound synthetic route of embodiment 1:

[0163]

[0164]Intermediate 1. 94.7g (0.486mol) of 2,3,4,5-tetrafluoronitrobenzene and 82g (0.534mol) of 4-piperidone hydrochloride were dissolved in 110mL of N-methylpyrrolidone (NMP), The solution was cooled to 5°C with an ice-water bath. Then slowly add 156.8g (0.712mol) of N,N-diisopropylethylamine (DIEA) dropwise into the above solution under stirring, control the temperature between 0 and 10°C, react for 30 minutes, and then rise to Room temperature, reaction overnight, TLC detection, the raw material completely disappeared. The reaction solution was slowly poured into 1.5L of water, a yellow solid product was precipitated, filtered, the filtered solid was washed 2-3 times with water, and then dried to obtain 140 g of intermediate 1 compound, yield: 90%. 1 H NMR (400MHz, CDCl 3 ): 7.74 (m, 1H); 3.73 (t, J = 6.0Hz, 4H); 2.66 (t, J = 6.0Hz, 4H). MS (m / z): 275 [M+H]...

Embodiment 2

[0174] Example 2. Compound structure

[0175]

[0176] Compound synthetic route of embodiment 2:

[0177]

[0178] Intermediate 6. 12.6g (36.8mmol) of the compound of Example 1 and 15.4mL (110.4mmol) of triethylamine were dissolved in 150mL of dichloromethane (DCM), cooled to 0°C in an ice bath under stirring, and slowly added dropwise to 5.7mL ( 73.6 mmol) of methanesulfonyl chloride. After the dropwise addition was completed, stirring was continued for 1 hour under an ice bath, 100 mL of saturated brine was added to the reaction solution, and the dichloromethane layer was separated. The dichloromethane layer was washed once with 100 mL of saturated ammonium chloride solution, the combined dichloromethane layers were washed once with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and most of the solvent was removed under reduced pressure. The wet solid was filtered, crushed and washed with 30 mL of ethyl acetate, stirred at 15 °C for one...

Embodiment 3

[0181] Example 3. Compound structure

[0182]

[0183] Embodiment 3 compound synthetic route:

[0184]

[0185] Intermediate 8

[0186] Method A. Under nitrogen protection, 187mg (1.00mmol) of N-Boc-3-aminoisoxazole was dissolved in 1mL of DMF, and then it was slowly added dropwise to NaH (content 60%, 48mg, 1.20mmol) in DMF (2mL) In the solution, the temperature was raised to 35°C, and the reaction was stirred for 15 minutes. Intermediate 6 (357 mg, 0.85 mmol) was dissolved in 1 mL of DMF, and then slowly added dropwise to the above reaction solution, and the system was heated to 50° C. for 1.5 hours. The reaction mixture was poured into 30 mL of ethyl acetate and washed with 10% NH 4 It was washed with aqueous Cl solution (2×30 mL), then washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the product was separated through a silica gel column (2% methanol / dichloromethane) to obtain 151 mg o...

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Abstract

The invention relates to a method and technology for synthesizing and producing an antibiotic medicament namely 1-(o-fluorophenyl) dihydropyridone. The type of compound can be used for treating infections of mammals. An entire preparation process comprises the following steps: i) transforming O-silanized N-(o-fluorophenyl)-4-piperidone into substituted 4-[4-(2,3-alkene) pyridine-1-]-radical-2-fluoronitrobenzene, wherein the latter can be reduced and acylated to generate carbamic acid ester; and ii) performing a reaction of the carbamic acid ester and an epoxy compound or chlorohydrin to generate corresponding 5-hydroxymethyl or substituted 5-aminomethyl oxazolidinone, wherein 5-aminomethyl oxazolidinone can be further transformed into antibiotic oxazolidinone with a structure I, and the definition of each group is as shown by the specification.

Description

field of invention [0001] The invention provides a method and process for the synthesis and production of a novel oxazolidinone derivative 1-(o-fluorophenyl)dihydropyridone. The compound has strong activity against widely distributed pathogenic bacteria, and can be applied to treating infection caused by bacteria in mammals. Background of the invention [0002] Due to the gradual increase in antibiotic resistance, the treatment of bacterial infections urgently requires novel antimicrobial compounds with novel modes of action. [0003] Among the newer antibiotic drugs, oxazolidinones are the latest class of synthetic compounds with activity against various pathogenic microorganisms. So far, linezolid (Zyvox R ) is the only antibiotic in this class that has been approved for the treatment of Gram-positive infections. Although this representative drug of oxazolidinones can be used for the treatment of microbial infections, its antibacterial activity is still not high enough ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10C07D413/14C07D211/74C07F7/18C07D211/86A61P31/04
CPCC07D413/10A61P31/04
Inventor 周峰王强M.F.戈德耶夫
Owner SHANGHAI MICURX LTD
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