The preparation method of 3-substituted phenyl-5-aminomethyl oxazolidin-2-one

A technology of aminomethyl oxazolidine and phenyl, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of inability to adapt to large-scale industrial production, harsh reaction conditions, many reaction steps, etc., and achieves improved safety production coefficient and synthesis efficiency. High, few-step effect

Active Publication Date: 2015-12-02
SUZHOU JINGYE MEDICINE & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] This method has many reaction steps and relatively harsh reaction conditions, and needs to use butyllithium reagent (in other similar methods, there are also reagents such as tert-butoxide lithium, methanesulfonyl chloride, sodium azide, etc.), which causes large pollution and low safety. ; As can be seen from this article, during the preparation of compound 4 in the formula, the reaction needs to be carried out at -78 ° C, which cannot be adapted to large-scale industrial production

Method used

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  • The preparation method of 3-substituted phenyl-5-aminomethyl oxazolidin-2-one
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  • The preparation method of 3-substituted phenyl-5-aminomethyl oxazolidin-2-one

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Effect test

Embodiment 1

[0041] Example 1: Synthesis of 3-substituted phenyl-5-aminomethyloxazolidin-2-one.

[0042] (1)

[0043]Add 39.2 g of compound (II) of 3-fluoro-4-morpholinoaniline, 31.5 g of R-epichlorohydrin (III) and 680 ml of ethanol into a 1000 ml four-neck flask. Heating to 50°C, stirring and reacting at 50-55°C for 24 hours. Cool to about 30°C for the next reaction.

[0044] (2)

[0045] Add the ethanol solution obtained in step (1) and 64g of dibenzylamine to a 1000ml four-necked flask, add 26.5g of sodium hydroxide solution (30%) under stirring, raise the temperature to 60°C, and stir for 12 hours. Ethanol was removed under reduced pressure. Cool to room temperature, add 200ml dichloroethane, 400ml water and 70g concentrated hydrochloric acid (36%), stir for 2-3hrs. Cool to about 10°C, filter with suction, and wash the solid with 100ml of dichloroethane and 150ml of water. Combine the filtrate and washings, separate the layers, and separate the organic phase. Add 300ml of d...

Embodiment 2

[0056] The ethanol solvent in the step (1) of Example 1 was replaced with tetrahydrofuran, and then according to the synthesis method of Steps (1)-(3) of Example 1, about 58 g of the target compound VIII was obtained, with a content of more than 99.0%, and a three-step yield of 60.9 %.

Embodiment 3

[0058] In the step (2) of embodiment one, the reaction temperature of the ethanol feed liquid obtained in the step (1) and dibenzylamine is raised to 100° C. in the presence of sodium hydroxide solution, and then according to the step (2), step (3 ) synthetic method to obtain about 55g of target compound VIII, three-step yield 57.7%.

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Abstract

The invention discloses a preparation method of 3-substituted phenyl-5-(aminomethyl) oxazolidin-2-one. The preparation method comprises the following steps of: enabling substituted aniline to react with (R)-chloro-epoxy propane to get (R)-3-substituted phenylamino-2-hydroxy-chloropropane, further reacting with dibenzyl amine to get (R)-3-substituted phenylamino-1-dibenzyl amino-2-propanol, cyclizing to get (S)-3-substituted phenyl-5-dibenzyl aminomethyl oxazolidin-2-one and finally performing hydrogenation and debenzylation to get (S)-substituted phenyl-5-(aminomethyl) oxazolidin-2-one. A compound obtained by the method disclosed by the invention is of an important intermediate for commercial production of oxazolidinone type antibacterial agents. The method for preparing the 3-substituted phenyl-5-(aminomethyl) oxazolidin-2-one through four-step reaction has the characteristics of few steps, simple operation, low cost and easiness in obtainment of raw materials, mild reaction conditions and the like; and by adopting the method, the production efficiency can be improved, the production energy consumption can be reduced, a safety production coefficient can be further improved, environmental pollution can be reduced, and the preparation method is of an environment-friendly and low-carbon green synthesis method.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of a key intermediate 3-substituted phenyl-5-aminomethyloxazolidin-2-one for the preparation of an oxazolidinone antibacterial agent. Background technique [0002] Oxazolidinone antibacterial agents are a new class of antibacterial agents whose mechanism of action is different from other antibacterial agents. 3-Substituted phenyl-5-aminomethyloxazolidin-2-ones are the key intermediates necessary for the synthesis of this class of drugs, and most of these compounds are obtained by acylation of amino groups to final products. [0003] The preparation method of 3-substituted phenyl-5-aminomethyl oxazolidin-2-one, the earliest method adopted by most researchers is to use substituted aniline as raw material, first react with benzyl chloroformate, and then transform to prepare to 3-substituted phenyl-5-hydroxymethyloxazolidin-2-one, and then...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/20
Inventor 沈建伟吴和明朱崇泉
Owner SUZHOU JINGYE MEDICINE & CHEM
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