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Novel preparation method of netaglinide oxazolone

A technology of linzolid and its compound, which is applied in the field of drug synthesis, can solve the problems of unfavorable industrial production, serious environmental pollution, and long reaction route, and achieve the effects of high stereoselectivity, high atom utilization rate, and low production cost

Inactive Publication Date: 2010-02-03
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The above method uses dangerous reaction reagent butyllithium or tert-butyllithium, highly toxic reagent phosgene, or uses expensive raw materials, and the reaction route is long, the environment is seriously polluted, and the cost is high, which is not conducive to industrial production

Method used

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  • Novel preparation method of netaglinide oxazolone
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  • Novel preparation method of netaglinide oxazolone

Examples

Experimental program
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Effect test

Embodiment 13

[0044] The synthesis of embodiment 13-fluoro-4-morpholine phenyl oxazolidinone

[0045] Weigh 3-fluoro-4-morpholine phenyl isocyanate (1.11g, 5mmol) and (R)-epichlorohydrin (0.51g, 5.5mmol) in a 25mL single-necked flask, add 10mL tetrahydrofuran and stir to dissolve, then add MgI 2 (2.5mmol), stirred at 50°C for 4h, added 5% sodium thiosulfate aqueous solution to quench the reaction, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was extracted with ethyl acetate-petroleum ether (V / V=1:15) recrystallized to obtain off-white solid 1.47g, yield 93%.

Embodiment 23

[0046] The synthesis of embodiment 23-fluoro-4-morpholine phenyl oxazolidinone

[0047] Weigh 3-fluoro-4-morpholine phenyl isocyanate (1.11g, 5mmol) and (R)-epichlorohydrin (0.51g, 5.5mmol) in a 25mL single-necked flask, add 10mL tetrahydrofuran and stir to dissolve, then add MgBr 2 (2.5mmol), heated and stirred at 50°C for 5h, added 5% sodium thiosulfate aqueous solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was washed with ethyl acetate-petroleum ether (V / V=1:15) recrystallized to obtain off-white solid 1.50 g, yield 95%.

Embodiment 33

[0048] The synthesis of embodiment 3-fluoro-4-morpholine phenyl oxazolidinone

[0049] Weigh 3-fluoro-4-morpholine phenyl isocyanate (1.11g, 5mmol) and (R)-epichlorohydrin (0.51g, 5.5mmol) in a 25mL single-necked flask, add 10mL tetrahydrofuran and stir to dissolve, then add MgCl 2 (2.5mmol), heated and stirred at 50°C for 8h, added 5% sodium thiosulfate aqueous solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was washed with ethyl acetate-petroleum ether (V / V=1:15) recrystallized to obtain off-white solid 0.94g, yield 60%.

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Abstract

The invention discloses a novel preparation method of netaglinide oxazolone shown in the formula (IV), which comprises the following steps: under the action of a catalyst A, enabling 3-fluorine-4-morpholine phenyl isocyanate shown in the formula (I) to react with (R)-epoxy chloropropane to obtain a compound (II), wherein the catalyst A is magnesium diiodide, magnesium dibromide, magnesium dichloride, magnesium perchlorate or magnesium trifluoromethanesulfonic acid; enabling the compound (II) to react with sodium azide to obtain a compound (III); reducing the compound (III) by hydrogenation, and then, acetylating the reduced compound (III) to obtain the compound (IV). In the invention, the low-cost and environment-friendly catalyst (Lewis acid magnesium) is used for catalyzing the cycloaddition reaction of the (R)-epoxy compound and the isocyanate to establish a mother nucleus structure of the netaglinide oxazolone by one step, thus the prepared netaglinide oxazolone has high stereoselectivity, does not need rigorous operation conditions, such as low temperature, no water, no oxygen and the like, has the advantages of moderate reaction conditions, simple and convenient operation, high utilization ratio of atoms, environment protection, low production cost and the like, and is suitable for industrialized production.

Description

(1) Technical field [0001] The invention relates to the field of drug synthesis, in particular to a new method for preparing antibacterial drug linzolid. (2) Background technology [0002] In recent years, various antibiotics and antibacterial agent-resistant bacteria have developed rapidly, for example, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), penicillin-resistant Streptococcus pneumoniae (PRSP), multiple The emergence of drug-resistant tuberculosis, especially vancomycin-resistant enterococci (VRE), has caused difficulties in clinical treatment. Since existing drugs are still difficult to effectively control such bacterial infections, medicinal chemists are working hard to develop new drugs against drug-resistant bacteria, and to design and screen new antibacterial drugs with new chemical structures, new mechanisms of action, or new targets. [0003] Linezolid is the first fully chemically synthesized oxa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/20B01J31/02B01J27/10B01J27/08B01J27/06A61P31/04
Inventor 张兴贤
Owner ZHEJIANG UNIV OF TECH
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