Synthesis method of 4-(4-aminophenyl)-3-morpholone

A technology of aminophenyl and morpholinone, which is applied in the field of synthesis of 4--3-morpholinone, an intermediate of rivaroxaban, can solve the problems of high raw material price, unsuitable for industrialized large-scale production, etc.

Inactive Publication Date: 2012-07-25
BEIJING GUANHONG TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are two reaction steps in this route, and the yield is relatively high, but the raw materials involved are also expensive, which is not suitable for the requirements of large-scale industrial production.

Method used

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  • Synthesis method of 4-(4-aminophenyl)-3-morpholone
  • Synthesis method of 4-(4-aminophenyl)-3-morpholone
  • Synthesis method of 4-(4-aminophenyl)-3-morpholone

Examples

Experimental program
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Effect test

example 1

[0032] Add 13.8g (0.1mol) of p-nitroaniline and 17.7g (0.12mol) of dichloroethyl ether into the reactor, heat to reflux, and react for 2.5 hours. The solid was washed with acetone and dried to obtain 17.1 g of 4-(4-nitrophenyl)-morpholine with a yield of 82%.

[0033] Add 20.8g (0.1mol) of 4-(4-nitrophenyl)-morpholine, 22.5g (0.25mol) of tert-butyl hydroperoxide, 2.3g of ethyl acetoacetate manganese salt and appropriate amount of tetrahydrofuran into the reaction kettle, and heat Reflux and react for 4.5 hours. After the reaction is completed, add activated carbon, stir for 30 minutes, filter, remove the solids, wash the filtrate with saturated aqueous sodium carbonate, add anhydrous magnesium sulfate and let it stand for drying, filter to remove the solids, spin the filtrate, and put it on a chromatographic column. -The washing solution of (4-nitrophenyl)-morpholinone segment was rotary evaporated to obtain 18.4 g of 4-(4-nitrophenyl)-morpholinone solid, with a yield of 83%....

example 2

[0036] Add 13.8g (0.1mol) of p-nitroaniline and 25.7g (0.11mol) of dibromoethyl ether into the reactor, heat to reflux, and react for 3 hours. The solid was washed with acetone and dried to obtain 16.9 g of 4-(4-nitrophenyl)-morpholine with a yield of 81%.

[0037]Add 20.8g (0.1mol) of 4-(4-nitrophenyl)-morpholine, 22.8g (0.3mol) of isopropyl hydroperoxide, 2.1g of ethyl acetoacetate manganese salt and appropriate amount of tetrahydrofuran into the reaction kettle, and heat Reflux and react for 3.5 hours. After the reaction is completed, add activated carbon, stir for 15 minutes, filter, remove the solid, wash the filtrate with saturated aqueous sodium carbonate, add anhydrous magnesium sulfate and let it stand for drying, filter to remove the solid, and the filtrate is rotary evaporated, put on a chromatographic column, and collect 4 -The washing solution of (4-nitrophenyl)-morpholinone segment was rotary evaporated to obtain 18.9 g of 4-(4-nitrophenyl)-morpholinone as a sol...

example 3

[0040] Add 13.8g (0.1mol) of p-nitroaniline and 20.3g (0.14mol) of dichloroethyl ether into the reactor, heat to reflux, and react for 1 hour. The solid was washed with acetone and dried to obtain 17.9 g of 4-(4-nitrophenyl)-morpholine with a yield of 86%.

[0041] 20.8g (0.1mol) 4-(4-nitrophenyl)-morpholine, 16.7g (0.16mol) pentyl hydroperoxide and 5.7g 4-cyclohexylbutyric acid manganese salt and appropriate amount of 1,4- Dioxane was added into the reactor, heated to reflux, and reacted for 4 hours. After the reaction is completed, add activated carbon, stir for 15 minutes, filter, remove the solid, wash the filtrate with saturated aqueous sodium carbonate, add anhydrous magnesium sulfate and let it stand for drying, filter to remove the solid, and the filtrate is rotary evaporated, put on a chromatographic column, and collect 4 -The washing solution of (4-nitrophenyl)-morpholinone segment was rotary evaporated to obtain 18.5 g of 4-(4-nitrophenyl)-morpholinone solid, with ...

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Abstract

The invention provides a synthesis method of an important intermediate 4-(4-aminophenyl)-3-morpholone of a new anticoagulant rivaroxaban, belonging to the field of chemical synthesis. The method comprises the following steps: 1) cyclizing nitroaniline and di-halogen aether to obtain 4-(4-nitrophenyl)-morpholine; 2) reacting 4-(4-nitrophenyl)-morpholine and organic hydroperoxide under the action of a catalyst to generate 4-(4-nitrophenyl)-morpholone; and 3) reducing the 4-(4-nitrophenyl)-morpholone into the under the action of a catalyst, wherein the mol yield of the three steps is higher than 49% (on the basis of nitroaniline). The synthesis method provided by the invention has the characteristics of accessible raw materials, low price, simple operation steps, mild reaction environment and the like, and is suitable for industrialized mass production; and the three wastes are easy to process.

Description

1. Technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a method for synthesizing rivaroxaban intermediate 4-(4-aminophenyl)-3-morpholinone. 2. Technical background [0002] The chemical structural formula of 4-(4-aminophenyl)-3-morpholinone is as follows: [0003] [0004] 4-(4-aminophenyl)-3-morpholinone (4-(4-Aminophenyl)-3-Morpholinone, hereinafter referred to as APMP) is an important intermediate for the synthesis of a new anticoagulant rivaroxaban. [0005] 4-(4-Aminophenyl)-3-morpholinone is an important intermediate in the synthesis of rivaroxaban. On the basis of consulting a large number of domestic and foreign literature, we report 4-(4- The synthesis method of aminophenyl)-3-morpholinone is summarized, and it is found that there are several kinds as follows. We analyze various methods from the price of reaction raw materials, the complexity of the reaction process, the level of reaction condition requirements, oper...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/32
Inventor 许波贺玉荣殷红
Owner BEIJING GUANHONG TECH
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