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Method of biocatalytically synthesizing 4-substituted oxazolidinone compound

A technology of oxazolidinone and biocatalysis, which is applied in the field of bioengineering to achieve the effect of broad application prospects

Active Publication Date: 2019-04-09
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the halohydrin dehalogenase catalysts that have been reported so far show a high degree of β-attack ring-opening regioselectivity in the process of catalyzing the ring-opening reaction of cyanate ions on epoxy compounds, that is, the obtained oxazolidinone The compounds are all 5-substituted oxazolidinones

Method used

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  • Method of biocatalytically synthesizing 4-substituted oxazolidinone compound
  • Method of biocatalytically synthesizing 4-substituted oxazolidinone compound
  • Method of biocatalytically synthesizing 4-substituted oxazolidinone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 4-phenyloxazolidinone synthesis: add 0.45g (dry weight) recombinant halohydrin dehalogenase, 176mg sodium cyanate to 30mL disodium hydrogen phosphate-potassium dihydrogen phosphate (50mM, pH 7.5) buffer solution; 300 μl of dimethyl sulfoxide (as a co-solvent) was dissolved in 108 μl of styrene oxide and added to the buffer. The reaction solution was placed in a temperature-controlled shaker at 30° C., and reacted at 250 rpm for 12 hours. After the reaction was completed, the reaction liquid was extracted with ethyl acetate (2×30 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1), and reduced Rotary steaming under pressure gave a white solid. 77% yield, 1 HNMR (400MHz, CDCl 3 )δ7.38(m, 5H), 6.21(s, 1H), 4.95(t, J=7.8Hz, 1H), 4.72(t, J=8.7Hz, 1H), 4.17(t, J=7.8Hz, 1H). 13 C NMR (100MHz, CDCl 3 ) δ 160.0, 139.6, 129.3, 128.9, 126.1, 72.7,...

Embodiment 2

[0028] 4-(3-fluorophenyl)-oxan-2-one synthesis: Add 0.45 g (dry weight) of recombinant halohydrin to 30 mL of disodium hydrogen phosphate-potassium dihydrogen phosphate (50 mM, pH 7.5) buffer Halogenase, 176 mg sodium cyanate; 102 microliters of 3-fluorostyrene oxide was dissolved in 300 microliters of dimethyl sulfoxide (as a co-solvent) and added to the buffer. The reaction solution was placed in a temperature-controlled shaker at 30° C., and reacted at 250 rpm for 12 hours. After the reaction was completed, the reaction liquid was extracted with ethyl acetate (2×30 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1), and reduced Rotary steaming under pressure gave a white solid. 66% yield, 1 H NMR (400MHz, CDCl 3 )δ7.35(dd, J=13.6,7.3Hz,1H),7.10(d,J=7.5Hz,1H),7.03(m,2H),6.89(s,1H),4.96(t,J=7.7 Hz,1H),4.71(t,J=8.7Hz,1H),4.17-4.09(m,1H). 13 C ...

Embodiment 3

[0032]4-(3-Chlorophenyl)-oxan-2-one synthesis: Add 0.45 g (dry weight) of recombinant halohydrin to 30 mL of disodium hydrogen phosphate-potassium dihydrogen phosphate (50 mM, pH 7.5) buffer Halogenase, 176 mg sodium cyanate; 108 microliters of 3-chlorostyrene oxide was dissolved in 300 microliters of dimethyl sulfoxide (as a co-solvent) and added to the buffer. The reaction solution was placed in a temperature-controlled shaker at 30° C., and reacted at 250 rpm for 12 hours. After the reaction was completed, the reaction liquid was extracted with ethyl acetate (2×30 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1), and reduced Rotary steaming under pressure gave a white solid. 65% yield, 1 H NMR (400MHz, CDCl 3 )δ7.32(m, 3H), 7.24-7.15(m, 1H), 6.83(s, 1H), 4.99-4.88(t, J=7.8Hz, 1H), 4.70(t, J=8.7Hz, 1H ), 4.12 (dd, J=8.3, 7.0Hz, 1H). 13 C N...

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Abstract

The invention discloses a biocatalytic technology of synthesizing a 4-substituted oxazolidinone compound by carrying out a reaction on a halohydrin dehalogenase catalyzed epoxy compound and cyanate. The reaction takes the epoxy compound as a primer, cyanate as a nucleophilic ring opening reagent and halohydrin dehalogenase which is originated from an Ilumatobacter coccineus strain and has high alpha-offensive ring opening area selectivity as a biocatalyst. The reaction is carried out in a water phase and is mild in reaction condition. The invention is the biocatalytic method of catalyzing theepoxy compound to synthesize the 4-substituted oxazolidinone compound by using the halohydrin dehalogenase for the first time. The method has a wide application prospect in design of an oxazolidinonedrug and green manufacturing aspect thereof.

Description

technical field [0001] The invention belongs to the technical field of bioengineering, and in particular relates to a method for synthesizing 4-substituted oxazolidinone compounds by a biological enzyme method; specifically, the present invention relates to utilizing biological enzymes to catalyze epoxy compounds and cyanates under mild conditions A biocatalytic technology for the synthesis of 4-substituted oxazolidinone compounds. Background technique [0002] Antibiotics and artificially synthesized antibacterial drugs are the first choice for human to treat microbial infectious diseases. According to statistics, clinical prescriptions for preventive antimicrobials account for more than half of the total consumption of antimicrobials. In recent years, the excessive use or even abuse of antibiotics has led to the increasingly serious problem of bacterial resistance, especially "methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE)", "peni...

Claims

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Application Information

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IPC IPC(8): C07D263/22C07D263/20C12P13/00
CPCC12P13/004C07D263/20C07D263/22
Inventor 万南微陈永正田嘉伟
Owner ZUNYI MEDICAL UNIVERSITY
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