A method for synthesizing 3-fluoro-4-(4-morpholinyl)aniline in a microchannel reactor

Abstract

The invention provides a method for synthesizing 3-fluoro-4-(4-morpholinyl)aniline by using a micro-channel reactor. The micro-channel reactor comprises a preheating module group composed of one or more parallely-connected preheating modules and a reaction module group composed of one or more tandemly-connected reaction modules, wherein the preheating module group is series connection with the reaction module group. The method comprises the following steps: separately preheating difluorobenzene, concentrated nitric acid and concentrated sulfuric acid, then subjecting the preheated difluorobenzene, concentrated nitric acid and concentrated sulfuric acid to a reaction in the reaction module group and carrying out treatment so as to obtain 3,4-difluoronitrobenzene; dissolving 3,4-difluoronitrobenzene in an organic solvent, adding organic base, dissolving morpholine in the organic solvent, carrying out preheating, allowing the obtained solution to enter the reaction module group for a reaction and carrying out treatment so as to obtain 4-(2-fluoro-4-nitrophenyl)morpholine; and dissolving 4-(2-fluoro-4-nitrophenyl)morpholine in ethyl acetate, adding a catalyst, carrying out preheating, allowing the obtained solution and hydrogen to enter the reaction module group for a reaction and carrying out treatment so as to obtain 3-fluoro-4-(4-morpholinyl)aniline. The method has the advantages of low energy consumption, high yield, high product purity, safety, flexibility, etc.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for synthesizing 3-fluoro-4-(4-morpholino)aniline. Background technique [0002] 3-Fluoro-4-(4-morpholinyl)aniline is the key intermediate of the currently synthetic antibiotic linezolid. The structure of linezolid is as follows: [0003] [0004] Linezolid, which was approved by the US FDA in 2000, is a bacterial protein synthesis inhibitor used to treat infections caused by Gram-positive (G+) cocci. The site and mode of action of linezolid are unique, so in positive bacteria with essential or acquired resistance characteristics, it is not easy to cross-resistance with other antibacterial drugs that inhibit protein synthesis, and it is not easy to induce bacterial resistance in vitro generation. It is an oxazolidinone antibiotic with good clinical effect and broad-spectrum drug resistance. Therefore, it is of great significance to explore a new method for the synt...

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Problems solved by technology

[0008] 1. Both the nitration reaction and the nucleophilic substitution reaction are strong exothermic reactions, and they need to be controlled at a relatively low temperature when operating in a conventional reactor. The heat released by the reaction cannot be taken away in time, and the reaction temperature cannot be accurately controlled. , Insufficient stirring of heterogeneous reaction and other disadvantages, it is easy to cause side reactions such as multi-nitration and oxidation, the process operation is very complicated, the amplification effect is obvious, the energy consumption is high, and the yield is low

[0009] 2. Catalytic hydrogenation reaction is a typical gas-liquid-solid three-phase heterogeneous reaction. When operating in a reactor, in order to ensure full contact between the three phases, it usually requires high temperature, high pressure and long-term reaction, which consumes a lot of energy. high, and since H 2 Flammable and explosive properties, if leakage occurs during production, it will pose a great safety hazard

At the same time, due to the long reaction time of catalytic hydrogenation, the surface structure of the catalyst has changed greatly, so it is difficult to directly recycle the catalyst

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