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Method for preparing 4-(4-aminophenyl)morpholin-3-one

A technology of aminophenyl and morpholine, applied in the preparation of organic compounds, carboxylic acid amide preparation, chemical instruments and methods, etc., can solve the problems of high activity of nitrohalogenated benzene, high price of bromoacetyl bromide, strong corrosion, etc.

Active Publication Date: 2020-02-04
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the activity of p-nitrohalogenated benzene is higher, while p-nitrohalogenated benzene and ethanolamine react to generate product p-nitroanilino ethanol, a small amount of by-product p-nitrophenoxyethylamine is generated, and product p-nitroanilino ethanol And the by-product p-nitrophenoxyethylamine continues to further condense with chloroacetyl chloride to lead to a series of by-products
When p-nitroaniline and ethylene oxide prepare 2-p-nitroanilino ethanol, it is easy to produce a double-substituted by-product 2,2-di(p-nitroanilino)ethanol, and the price of bromoacetyl bromide is high and corrosive. Not conducive to operation
This route is not conducive to the preparation of high-purity 4-(4-aminophenyl) morpholin-3-one

Method used

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  • Method for preparing 4-(4-aminophenyl)morpholin-3-one
  • Method for preparing 4-(4-aminophenyl)morpholin-3-one
  • Method for preparing 4-(4-aminophenyl)morpholin-3-one

Examples

Experimental program
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Effect test

Embodiment 1

[0091] Embodiment 1: the preparation of p-acetamidoaniline (Ⅲ1)

[0092] Into a 500 ml four-necked flask connected with a stirrer, a thermometer, and a condenser tube, add 360 g of tetrahydrofuran, 69.0 g (0.5 mole) of p-nitroaniline, and 61.2 g (0.6 mole) of acetic anhydride, heat at 60-65 ° C Stir the reaction for 4 hours, detect that the reaction of p-nitroaniline is complete, cool to 20-25 ° C, transfer the resulting reaction liquid to a 1-liter autoclave, wash the four-necked flask with 20.0 grams of water, and transfer the washing liquid to the autoclave. Add 0.8 gram of 5% palladium carbon catalyst (water content 50%), after nitrogen replacement 3 times, stir reaction at internal temperature 40-45 ℃, hydrogen pressure 2-4 atmospheric pressure for 5 hours, cool to room temperature, filter recovery catalyst, use Wash the filter cake with 20 grams of methanol, recover tetrahydrofuran, methanol and aqueous acetic acid from the filtrate, and wash the residue with methyl tert...

Embodiment 2

[0093] Embodiment 2: the preparation of p-acetamidoaniline (Ⅲ1)

[0094] To a 500 ml four-neck flask connected with a stirrer, a thermometer and a condenser tube, add 400 grams of toluene, 69.0 grams (0.5 moles) of p-nitroaniline, and 61.2 grams (0.6 moles) of acetic anhydride, heat at 65-70 ° C Stir the reaction for 5 hours, cool to 20-25°C, transfer the resulting reaction liquid to a 1-liter autoclave, wash the four-necked flask with 20.0 grams of water, transfer the washing liquid to the autoclave, and add 8.0 grams of 50% Raney nickel Catalyst (water content 50%), after nitrogen replacement 3 times, at internal temperature 45-50 ℃, hydrogen pressure 2-4 atmospheric pressure under stirring reaction 6 hours, cool to room temperature, filter recovery catalyst, wash filter cake with 20 grams of methanol, Toluene, methanol, and aqueous acetic acid were recovered from the filtrate, and the residue was washed with methyl tert-butyl ether to obtain 70.6 g of p-acetamidoaniline (Ⅲ1...

Embodiment 3

[0095] Embodiment 3: the preparation of p-acetamidoaniline (Ⅲ1) (separation of p-nitroacetamidobenzene method)

[0096] In the 500 milliliter four-necked flask that is connected with stirrer, thermometer, condenser tube, add 360 grams of dichloromethane, 69.0 grams (0.5 moles) of p-nitroaniline, 61.2 grams (0.6 moles) of acetic anhydride, stir reaction at room temperature for 4 hours , filtered, and the filter cake was washed with 20 grams of dichloromethane to obtain 86.6 grams of p-nitroacetamidobenzene (II), with a yield of 96.1%. The liquid phase purity is 99.5%.

[0097] In the autoclave, successively add 450g tetrahydrofuran, 86.6 grams of p-nitroacetamidobenzene (II) and 8.0 grams of 50% Raney nickel catalyst (water content 50%), after nitrogen replacement 3 times, at an internal temperature of 45-50 ° C, Stir the reaction under 2-4 atmospheres of hydrogen pressure for 8 hours, cool to room temperature, filter and recover the catalyst, wash the filter cake with 20 gram...

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Abstract

The invention relates to a method for preparing 4-(4-aminophenyl)morpholin-3-one. The method comprises the steps of subjecting p-nitroaniline, which serves as a raw material, to an amidation reaction,performing a catalytic hydrogenation reaction, so as to obtain p-acyl substituted aminoaniline, then, subjecting the p-acyl substituted aminoaniline and 1,4-dioxan-2-oneto an amidation reaction, performing a halogenating reaction or a sulfonylation reaction so as to prepare N-(2-substituent ethyl-oxo-acetyl)p-acyl substituted aminoaniline, then, carrying out a condensation cyclization reaction inthe presence of an alkali so as to obtain 4-(4-substituted acyl aminophenyl)morpholin-3-one, and finally, carrying out acyl protective group removing, thereby obtaining a target product. According tothe method, the raw materials employed are cheap and readily available, the operation is simple and convenient, and the cost is low. An involved reaction of each step is high in activity and high inspecificity, reactions are easily performed, and the product is high in purity and high in yield.

Description

technical field [0001] The invention relates to a method for synthesizing morpholin-3-one derivatives, in particular to a method for preparing 4-(4-aminophenyl)morpholin-3-one, which can be used to prepare rivaroxaban , belonging to the field of pharmaceutical biochemical industry. Background technique [0002] Rivaroxaban, known in English as Rivaroxaban, is a new oral anticoagulant drug that is absorbed orally and has a long-lasting effect. It is used to prevent and treat venous thrombosis. It has a wide therapeutic range and does not require routine coagulation function monitoring. The world's first direct factor Xa inhibitor developed for Bayer was approved by the US Food and Drug Administration (FDA) in 2011. Clinically, it is mainly used to prevent the formation of deep vein thrombosis and pulmonary thrombosis in patients after hip and knee replacement. It can also prevent stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation...

Claims

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Application Information

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IPC IPC(8): C07D265/32
CPCC07D265/32C07C231/02C07C235/16Y02P20/55
Inventor 刘月盛戚聿新陈军潘秉辰钱余锋
Owner XINFA PHARMA
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