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A kind of preparation method of 3-morpholinone

A technology of morpholinone and hydroxyacetate, which is applied in the field of preparation of 3-morpholinone, can solve problems such as process safety hazards, difficulty in batch production, and severe reactions, and achieve high purity, less side reactions, and easy-to-obtain raw materials Effect

Active Publication Date: 2019-04-05
SHANGHAI KELY BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method requires the use of sodium hydride or metal sodium, which reacts violently and emits a large amount of hydrogen gas, which is very easy to burn and explode. The process has major safety hazards, and it is difficult to industrialize mass production.

Method used

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  • A kind of preparation method of 3-morpholinone
  • A kind of preparation method of 3-morpholinone
  • A kind of preparation method of 3-morpholinone

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preparation example Construction

[0025] The invention provides a kind of preparation method of 3-morpholinone, comprises the following steps:

[0026] (1) Dehydrohalogenation of 2-haloethylamine hydrohalide in the presence of an organic solvent, after mixing the resulting reaction system with 2-hydroxyacetate, carry out amine transesterification to obtain 2-(2 - glycolamido) haloethane;

[0027] (2) The 2-(2-hydroxyacetamido) haloethane in the step (1) is subjected to a ring-closing reaction in the presence of an alkali reagent and an organic solvent to obtain 3-morpholinone.

[0028] In the present invention, 2-haloethylamine hydrohalide is dehydrohalogenated in the presence of an organic solvent, and the resulting reaction system is mixed with 2-hydroxyacetate to perform amine transesterification to obtain 2-(2- Glycolamido) haloethanes.

[0029] In the present invention, the 2-haloethylamine hydrohalide preferably includes 2-chloroethylamine hydrochloride or 2-bromoethylamine hydrobromide. In the presen...

Embodiment 1

[0047] Stir and mix 116g (1.0mol) of 2-chloroethylamine hydrochloride with 300mL of dichloromethane, cool in an ice-water bath to 10°C, add 40g of sodium hydroxide (1.0mol) in batches under nitrogen protection, and control the temperature of the system not to exceed 20°C, after adding, stir for 30 minutes to dehydrochloride; add 114.5 g (1.1 mol) of ethyl 2-hydroxyacetate dropwise to the obtained reaction system containing 2-chloroethylamine, after dropping, react at room temperature for 9 hours, GC detection 2 - Chloroethylamine is completely reacted; the resulting system is filtered, the filtrate obtained is washed with 100 mL of water, the aqueous phase in the material obtained after washing is separated, the aqueous phase obtained is extracted with 100 mL of dichloromethane, and the organic phase obtained is After drying with anhydrous sodium sulfate and distilling off the solvent under reduced pressure, 2-(2-hydroxyacetamido)chloroethane was obtained.

[0048] Mix the 2-(...

Embodiment 2

[0051] Stir and mix 205g (1.0mol) of 2-chloroethylamine bromate and 800mL of dichloromethane, cool in an ice-water bath at 15°C, add 138.2g of potassium carbonate (1.0mol) in batches under nitrogen protection, and control the temperature of the system not to exceed 20°C, after adding, stir for 30 minutes to remove hydrogen bromide; add 156 g (1.5 mol) of ethyl 2-hydroxyacetate dropwise to the obtained reaction system containing 2-bromoethylamine, after dropping, react at room temperature for 9 hours, and detect by GC The reaction of 2-bromoethylamine is complete; the resulting system is filtered, and the filtrate obtained is washed with 200 mL of water, the water phase in the material obtained after washing is separated, and the obtained water phase is extracted with 150 mL of dichloromethane, and the obtained organic The phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2-(2-hydroxyacetamido)bromoethane.

[0052]...

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Abstract

The invention provides a method for preparing 3-morpholone. The method comprises the steps that halogen hydride removing is carried out on 2-halogenated ethylamine hydrohaloate under the condition oforganic solvent existing, an obtained reaction system and 2-glycollic acid ester are mixed and then subjected to amine ester exchange reaction to obtain 2-(2-hydroxyacetamido) halothane; ring closurereaction is carried out on the 2-(2-hydroxyacetamido) halothane under the condition of alkali reagent and organic solvent existing to obtain the 3-morpholone. The method for preparing the 3-morpholonehas the advantages that the technology side reaction is less, the product purification is convenient; the operation is simple, the safety is high, the method is environmentally friendly; raw materials are obtained easily, the price is low; the product yield is high (reaches 75.5%), the purity is high (reaches 99% or above), the method is suitable for the industrialized batch production, and the industrialized prospect is good.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediate raw materials, in particular to a preparation method of 3-morpholinone. Background technique [0002] Rivaroxaban (Rivaroxaban), the chemical name is 5-chloro-nitrogen-((5S)-2-oxo-3-[-4-(3-oxo-4-morpholinyl)phenyl]-1,3 -Azolidin-5-yl-2-thiophene-carboxamide, trade name Xarelto (Xarelto), is a new type of oral anticoagulant factor Xa drug jointly developed by Bayer AG of Germany and Johnson & Johnson of the United States, 2008 First launched in Canada in 2009, it is mainly used for the prevention and treatment of various thromboembolic diseases, such as the prevention of pulmonary embolism (PE) and deep vein thrombosis (DVT) in adult patients after elective hip or knee replacement. One of the most promising antithrombotic drugs. [0003] 3-Morpholinone is the key raw material for the preparation of rivaroxaban. At present, 3-morpholinone has the following sever...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/32
CPCC07D265/32
Inventor 李海林王世运张建现彭自祥张明明
Owner SHANGHAI KELY BIOPHARMACEUTICAL CO LTD
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