Method for synthesizing 3-fluoro-4-(4-morpholinyl)aniline by using micro-channel reactor

A micro-channel reactor, morpholine-based technology, applied in organic chemistry and other directions, can solve problems such as polynitration, complex process operation, and oxidation.

Active Publication Date: 2017-02-15
HEILONGJIANG XINCHUANG BIOLOGICAL TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

Method used

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  • Method for synthesizing 3-fluoro-4-(4-morpholinyl)aniline by using micro-channel reactor
  • Method for synthesizing 3-fluoro-4-(4-morpholinyl)aniline by using micro-channel reactor
  • Method for synthesizing 3-fluoro-4-(4-morpholinyl)aniline by using micro-channel reactor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] (1) Weigh 300g of o-difluorobenzene as material 1, measure 400ml of concentrated nitric acid as material 2, and measure 600mL of concentrated sulfuric acid as material 3;

[0077] (2) The flow velocity of control material 1 is 8ml / min; The flow velocity of control material 2 is 12min / min; The flow velocity of control material 3 is 18min / min; Reaction temperature is 20 ℃, and the mol ratio of o-difluorobenzene and nitric acid is 1 :2.5; The mol ratio of nitric acid and the vitriol oil is 1:2.0; The residence time of reaction is 65s;

[0078](3) After each strand of material in the reactor reaches a steady state, collect the reaction solution flowing out from the reactor outlet, and feed the corresponding reaction solution of material 1 (that is, 240ml of material 1, 275.0g of o-difluorobenzene) for 30 minutes For example, separate the liquid, keep the organic phase, extract the acid layer once with 300ml of dichloromethane, combine the organic phases, add 300ml of 10% Na...

Embodiment 2

[0086] In the screening and optimization process of process parameters, we explored the parameters such as the concentration of the reaction raw materials, molar ratio, residence time, etc., and changed the corresponding parameters of the corresponding steps on the basis of the operation steps in Example 1, and kept other parameters unchanged. , the results are summarized as follows:

[0087] 1. Nitrification reaction:

[0088]

[0089] 2. Nucleophilic substitution reaction:

[0090]

[0091] 3. Catalytic hydrogenation reaction:

[0092]

[0093]

[0094] 4. Pd / C recovery application experiment:

[0095]

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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...

Claims

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Application Information

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IPC IPC(8): C07D295/12
CPCC07D295/12
Inventor 任吉秋安永生杨昆李黛凤
Owner HEILONGJIANG XINCHUANG BIOLOGICAL TECH DEV CO LTD
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