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Preparation method of 4-(4-aminophenyl)-3-molindone

A technology of aminophenyl and morpholinone, which is applied in the field of preparation of 4--3-morpholinone, can solve the problems of not being suitable for large-scale industrial production, not being suitable for large-scale industrial production, difficult amidation reaction, etc. Good quality, low price, and improved reaction efficiency

Active Publication Date: 2018-10-16
上海科利生物医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route reaction step has two steps, and productive rate is higher, but in fact, in 4-nitroaniline, the deactivation of amino group by nitro group is very serious, and amidation reaction is difficult to carry out, and the raw material involved is also expensive at the same time, Not suitable for the requirements of industrialized mass production
[0025] 4-(4-aminophenyl)-3-morpholinone is the key intermediate of the method for synthesizing rivaroxaban. At present, the technological routes reported at home and abroad are not suitable for the requirements of industrialized large-scale production, and there are difficult reactions and operability. Poor performance, high production cost, unfavorable to environmental protection

Method used

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  • Preparation method of 4-(4-aminophenyl)-3-molindone

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Embodiment 1

[0068] The present embodiment prepares 4-(4-aminophenyl)-3-morpholinone through the following steps

[0069] (1) Mix 1 mole of 2-bromoethylamine hydrobromide with 500 ml of acetonitrile, cool in an ice-water bath to 10°C, add 1 mole of anhydrous potassium carbonate in batches under nitrogen protection, and control the temperature of the system not higher than 20°C, after the addition is complete, stir for 30 minutes to remove potassium bromide by filtration, then add 1 mole of anhydrous potassium carbonate, and add 1.2 moles of p-fluoronitrobenzene dropwise with stirring at room temperature. After dropping, the temperature was raised to 45°C for condensation reaction for 8h. GC detected that the reaction of 2-bromoethylamine was complete. The acetonitrile solvent was concentrated and distilled to dryness under reduced pressure. Add 300 ml of ethyl acetate and 200 ml of distilled water, stir for 15 minutes and then separate the layers. The aqueous phase was discarded, and th...

Embodiment 2

[0077] The present embodiment prepares 4-(4-aminophenyl)-3-morpholinone through the following steps

[0078] (1) Mix 1 mole of 2-chloroethylamine hydrogen hydrochloride with 500 milliliters of acetonitrile, cool in an ice-water bath to 10°C, add 1 mole mass of anhydrous cesium carbonate in batches under nitrogen protection, and control the temperature of the system not higher than 20°C, after the addition is complete, stir for 30 minutes to remove cesium chloride by filtration, then add 1 mole of anhydrous cesium carbonate, and add 2 moles of p-fluoronitrobenzene dropwise with stirring at room temperature. After dropping, heat up to 80°C for condensation reaction for 5h. GC detected that the reaction of 2-chloroethylamine was complete. The acetonitrile solvent was concentrated and distilled to dryness under reduced pressure. Add 300 ml of ethyl acetate and 200 ml of distilled water, stir for 15 minutes and then separate the layers. The aqueous phase was discarded, and the o...

Embodiment 3

[0086] The present embodiment prepares 4-(4-aminophenyl)-3-morpholinone through the following steps

[0087] (1) Mix 1 mole of 2-bromoethylamine hydrobromide with 500 ml of acetonitrile, cool in an ice-water bath to 10°C, add 1 mole of anhydrous potassium carbonate in batches under nitrogen protection, and control the temperature of the system not higher than 20°C, after the addition is complete, stir for 50 minutes to remove potassium bromide by filtration, then add 1.5 moles of anhydrous potassium carbonate, and add 0.5 moles of p-fluoronitrobenzene dropwise with stirring at room temperature. After dropping, heat up to 35°C for condensation reaction for 10h. GC detected that the reaction of 2-bromoethylamine was complete. The acetonitrile solvent was concentrated and distilled to dryness under reduced pressure. Add 250 ml of ethyl acetate and 180 ml of distilled water, stir for 10 minutes and then separate the layers. The aqueous phase was discarded, and the organic phase...

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Abstract

The invention provides a preparation method of 4-(4-aminophenyl)-3-molindone. The preparation method has the advantages that reaction steps with high risk and high environmental pressure are omitted,especially the use of mixed acid and chloroacetyl chloride is avoid, so that the pressure of environmental protection is reduced; in addition, the use of strong oxidants such as potassium permanganateis avoided, so that the production of by-products is reduced, the synthesis yield is high, the product quality is good and the purification of reaction post treatment is facilitated; besides, all thesteps related in the reaction process are easy to carry out, so that the reaction in which passivation effect of functional groups and the like are difficult to generate in an existing method is avoided, for example, the route which takes p-nitroaniline as a raw material to carry out substitution reaction is almost impossible to perform; besides, the selected raw materials such as p-fluoronitrobenzene and bromoethylamine hydrobromide, disclosed by the invention are easy to obtain; compared with the molindone and other raw materials involved in the existing method, the preparation method is low in price and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a preparation method of 4-(4-aminophenyl)-3-morpholinone. Background technique [0002] 4-(4-aminophenyl)-3-morpholinone is the key raw material for the preparation of rivaroxaban. 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] The mechanism of action of rivaroxaban is...

Claims

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Application Information

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IPC IPC(8): C07D265/32
CPCC07D265/32
Inventor 李海林王世运张建现彭自祥张明明
Owner 上海科利生物医药有限公司
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