Green synthesis method of 4-aminomorpholine under bimetal-carbonic acid system

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

[0001] technical field

[0002] 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

[0003] 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. WO2...

Examples

Embodiment 1

[0027] 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

[0029] 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

[0031] 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 rectification bottle, firstly the water in the reaction system was evaporated under reduced pressure, and then the temperature ...

[0001] technical field

[0002] 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

[0003] 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. WO2...

Examples

Embodiment 1

[0027] 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

[0029] 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

[0031] 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 rectification bottle, firstly the water in the reaction system was evaporated under reduced pressure, and then the temperature ...

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