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Green Synthesis of 4-Aminomorpholine in Bimetallic Carbonic Acid System

A technology of aminomorpholine and synthesis method, applied in the direction of organic chemistry, can solve the problems of increasing process cost, unfavorable to the environment, poor extraction effect, etc., achieve good economic and social benefits, avoid the use of organic reagents, typical Effect of by-product morpholine reduction

Inactive Publication Date: 2015-10-21
XIHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The first type of ring-closing method for synthesizing 4-aminomorpholine has basically no application value due to low reaction selectivity, many by-products, and extremely low yield, and is gradually eliminated.
The third type of synthesis method is gradually eliminated due to the low synthesis yield and high difficulty of synthesis due to the raw material 4-nitromorpholine.
Since there is water at the end of the reaction system and the product (N-aminopiperidine / piperazine / morpholine, etc.) has high polarity and good water solubility, the product is not easy to extract in the water phase, so the extraction efficiency is low and the extraction effect is not good
In addition, the alkali neutralization process produces a large amount of inorganic salt (sodium chloride) or organic salt (sodium acetate), and finally forms a large amount of solid waste residue
Process waste residues such as sodium chloride are not conducive to the environment if they are directly discharged, and further comprehensive utilization of resources will greatly increase process costs

Method used

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  • Green Synthesis of 4-Aminomorpholine in Bimetallic Carbonic Acid System

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Nitrosation reaction of morpholine (refer to the literature Synthetic Communications; vol.40; nb.5; (2010); P654 - 660, see Example 1 for details): add 600ml of solvent dichloromethane in the reaction bottle, at 20°C Add 87.15g (1.0mol) of morpholine, 82.80g (1.2mol) of sodium nitrite, and 17.36g of p-toluenesulfonic acid in sequence. After the TLC board monitors the complete reaction of the raw materials, the reaction solution is poured into 600ml of water, and 20% sodium hydroxide aqueous solution is used. Neutralize to pH=7, separate the liquids, extract the separated aqueous layer with dichloromethane multiple times, and remove the solvent dichloromethane from the combined organic phase under reduced pressure, and the obtained product is directly used in the next step of nitroso reduction reaction.

Embodiment 2

[0028] Synthesis of 4-aminomorpholine: Add the above-mentioned 4-nitrosomorpholine (synthesized according to Example 1, starting material morpholine is 1 mol) into a closed three-necked bottle with a carbon dioxide ventilation device and a gas flow meter 500ml of water and 5.0g of ammonium chloride were added in sequence, and the stirring was started and carbon dioxide gas was introduced into the system at a rate of 0.4 liters per minute. After a period of ventilation, the temperature was raised to 40°C, and 4.4g of 5% Pd / C reducing agent, and then add 128.6 g (2.0mol ) of Zn powder to the system in batches, and keep the temperature between 35-45°C during the process of adding Zn powder. Continue the reaction after the addition is complete. After the GC detects that the 4-nitrosomorpholine has reacted completely, stop the aeration, filter out the Pd / C and Zn slag, and wash the solid slag once with water. The combined filtrates were transferred to a rectification bottle, firstl...

Embodiment 3

[0030] Synthesis of 4-aminomorpholine: Add the above-mentioned 4-nitrosomorpholine (synthesized according to Example 1, starting material morpholine is 1 mol) into a closed three-necked bottle with a carbon dioxide ventilation device and a gas flow meter Then add 500ml of water and 5.0g of ammonium chloride to it in turn, start stirring and pass carbon dioxide gas into the system at a rate of 0.4 liters / min, after a period of ventilation, heat up to 40°C, and then Add 128.6 g (2.0 mol ) of Zn powder in batches, and keep the temperature between 35-45°C during the process of adding Zn powder. Continue the reaction after the addition is complete. After the GC detects that the 4-nitrosomorpholine has reacted completely, stop the aeration, filter out the Pd / C and Zn slag, and wash the solid slag once with water. The combined filtrates were transferred to a rectifying flask, firstly the water in the reaction system was distilled off under reduced pressure, and then the temperature w...

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Abstract

The invention discloses a synthesis method for preparing 4-aminomorpholine through reducing 4-nitrosomorpholine by using zinc powder-palladium / carbon bimetals. The synthesis method comprises the steps of with 4-nitrosomorpholine as a starting raw material, carrying out reduction reaction under a weak acid system by using a zinc powder-palladium / carbon bimetal catalyst, wherein the weak acid system is formed by carbon dioxide; carrying out simple aftertreatment to obtain a target product, i.e., 4-aminomorpholine with high yield and good product quality. Compared with the prior art, the synthesis method has the advantages that carbon dioxide gas is introduced to a water-containing reaction system in the reaction process to form carbonic acid which is more environment-friendly than acetic acid and hydrochloric acid.

Description

technical field [0001] The invention relates to the synthesis of a 4-aminomorpholine pharmaceutical intermediate, more precisely a method for preparing 4-aminomorpholine by reducing 4-nitrosomorpholine with zinc powder-palladium carbon double metal. Background technique [0002] 4-Aminomorpholine is an important fine chemical intermediate and is widely used in the fields of medicine and pesticides. For example, the recent literature Journal of Medicinal Chemistry, 2012, vol.55, nb.4, P1721-1730, reported that a series of carbonic anhydrase inhibitors were synthesized using 4-aminomorpholine as an important synthetic intermediate. WO20130050426 A1, 2013 reported the synthesis of a series of dithiocarbamate carbonic anhydrase inhibitors using 4-aminomorpholine as an intermediate. US20130225554 A1, 2013 reported the synthesis of a class of new bicyclic compounds used as antibacterial agents and enzyme inhibitors using 4-aminomorpholine as an intermediate. WO2011012389...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/30
CPCC07D295/30
Inventor 杨维清马梦林张园园黄继红任川洪
Owner XIHUA UNIV