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Oxazolidinone antibiotic containing parallel rings

An alkyl and alkylamine-based technology, applied in the field of medicine, can solve the problems of linezolid drug resistance, single oxazolidinone antibiotics, and inability to meet clinical medication requirements

Inactive Publication Date: 2011-08-17
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, clinically, the drug resistance of Gram-positive bacteria is becoming more and more serious, and the clinical drug variety of oxazolidinone antibiotics is very single, which cannot meet the clinical requirements, and the drug resistance of linezolid is also emerging

Method used

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  • Oxazolidinone antibiotic containing parallel rings
  • Oxazolidinone antibiotic containing parallel rings
  • Oxazolidinone antibiotic containing parallel rings

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0161] Example 1 (S)-N-[[3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Base]-2-oxo-5-oxazole Preparation of alkyl] methyl] acetamide

[0162]

[0163] Add 30 mL of 1,4-dioxane to the dry reaction flask, (S)N-[[3-(3-fluoro-4-bromophenyl)-2-oxo-5-oxazolidinyl ] methyl] acetamide 3.31g (10mmol), bis-valeryl diborane 2.54g (10mmol), potassium acetate 0.98g (10mmol), feed argon into the reaction flask, then add Pd (PPh 3 ) 2 Cl 2 0.3g, continue to feed argon into the reaction solution, stir the reaction overnight at 90°C, cool to room temperature, filter with diatomaceous earth, extract with ethyl acetate and brine, dry and concentrate the organic layer with anhydrous sodium sulfate, and precipitate a gray solid , 3.22 g of the product was obtained with a yield of 85.2%. ((S)-N-[[3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 used in the following examples -base) phenyl]-2-oxo-5-oxazolidinyl] methyl] the preparation of acetamide is prepare...

Embodiment 2

[0164] Example 2N-[[(5S)-3-[4-[1-[(1H-1,2,3-triazol-5-yl)methanamine]-2,3-two Hydrogen-1H-inden-5-yl]-3-fluorophenyl]-2- Preparation of oxo-5-oxazolidinyl]methyl]acetamide hydrochloride (compound 1 hydrochloride)

[0165]

[0166] (1) Preparation of 5-bromo-N-(2-propynyl)-2,3-dihydro-1H-inden-1-amine

[0167]

[0168] Dissolve propargylamine (6.6g, 0.12mol) and 5-bromo-1-indanone (22.9g, 0.109mmol) in 1,2-dichloroethane (300mL), and add to it under an ice-water bath Add NaBH(OAc) 3 (43.3g, 203mmol), after the addition, the mixture was stirred and reacted at room temperature for 40 hours, the organic phase was washed with water (50mL×2) and NaCl (150mL×2) successively, dried over anhydrous magnesium sulfate, and the organic phase was used directly without purification in the next step.

[0169] (2) Preparation of tert-butyl 5-bromo-2,3-dihydro-1H-inden-1-yl (2-propynyl) carbamate

[0170]

[0171] 5-Bromo-N-(2-propynyl)-2,3-dihydro-1H-inden-1-amine (8.9 g, 0.0...

Embodiment 3

[0186] Example 3N-[[(5S)-3-[4-[1-[2-(1H-1,2,3-triazol-5-yl)ethyl]indoline-5-yl]-3 -Fluorophenyl]-2-oxo - Preparation of 5-oxazolidinyl] methyl] acetamide (compound 2)

[0187]

[0188] (1) Preparation of 3-butynyl methanesulfonate

[0189]

[0190] In a 250mL reaction flask, dissolve 0.500g (7.13mmol) of 3-butyn-1-ol and 2.17g (21.4mmol) of triethylamine with 90mL of dichloromethane, and slowly add methanesulfonyl chloride 1.06 g (9.23mmol), added dropwise for about 30 minutes, stirred at room temperature overnight (16 hours) after removing the cooling bath, the organic phase was washed with 1M HCl (aqueous solution) and sodium chloride successively, then dried with anhydrous magnesium sulfate, and filtered After the solvent was removed under reduced pressure, 1.02 g of oily 3-butynyl methanesulfonate was obtained, with a yield of 96%.

[0191] (2) Preparation of 5-bromo-1-(3-butynyl)indoline

[0192]

[0193] Add Na to a toluene solution (40mL) of 4.95g (25mmo...

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Abstract

The invention belongs to technical field of medicaments, in particular to relates to an oxazolidinone antibiotic containing parallel rings as shown in a general formula (I) and a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1,R2, R3, R4, R5, R6, an A ring, a B ring and -Y- are defined in the specification. The invention also relates to a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds in preparing medicaments for treating and / or preventing infectious diseases.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to oxazolidinone antibiotics containing parallel rings, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and these compounds Use in the preparation of medicines for treating and / or preventing infectious diseases. 2. Background technology [0002] Oxazolidinone antibacterial drugs are a new type of chemically synthesized antibacterial drugs developed after sulfonamides and fluoroquinolones, which can inhibit multi-drug resistant Gram-positive bacteria. [0003] Linezolid is the first marketed oxazolidinone antibiotic, which has a strong inhibitory effect on Gram-positive bacteria and has no cross-resistance with other antibacterial drugs. The unique mechanism of action inhibits the early stages of bacterial protein synthesis. It is mainly used for the treatment...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D413/14C07D413/10C07D417/14C07D471/04C07D513/04A61K31/422A61K31/4709A61K31/4725A61K31/428A61K31/423A61K31/498A61K31/517A61K31/435A61K31/437A61P31/04
CPCC07D471/04C07D413/12C07D413/14C07D513/04C07D417/14A61P31/04
Inventor 黄振华
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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