Preparation method of 4-(nitrobenzophenone)-3-morpholone and method for preparing rivaroxaban by using 4-(nitrobenzophenone)-3-morpholone

A technology of nitrophenyl and morpholinone is applied in the field of preparation of rivaroxaban and intermediates thereof, and achieves the effects of saving labor cost, simple operation process and high product yield

Active Publication Date: 2014-08-13
山东康美乐医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] In order to solve the above prior art preparation of 4-(nitrophenyl)-3-morpholinone, the process is cumbersome, the cost is high, and each step of product post-treatment Complicated problems, the present invention provides a method for preparing 4-(nitrophenyl)-3-morpholinone in one pot with low raw material price
[0021] In order to solve the operational safety problems of raw materials in the preparation of rivaroxaban in the above prior art, the process is not easy to industrialized production, the output is not high and the price of raw materials is high Problem, the present invention provides a method for preparing rivaroxaban with low raw material price, non-toxic and harmless, easy industrialization and high yield

Method used

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  • Preparation method of 4-(nitrobenzophenone)-3-morpholone and method for preparing rivaroxaban by using 4-(nitrobenzophenone)-3-morpholone
  • Preparation method of 4-(nitrobenzophenone)-3-morpholone and method for preparing rivaroxaban by using 4-(nitrobenzophenone)-3-morpholone
  • Preparation method of 4-(nitrobenzophenone)-3-morpholone and method for preparing rivaroxaban by using 4-(nitrobenzophenone)-3-morpholone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Preparation of 4-(nitrophenyl)-3-morpholinone

[0049] In a 1000mL reaction flask, heat p-chloronitrobenzene (47.1g, 0.3mol) and potassium carbonate (144.9g, 1.05mol) in 500mL of acetonitrile to 60°C, dropwise add ethanolamine (20.2g, 0.33mol) to react 6 Hour. Cool down to 0°C, add chloroacetyl chloride (37.3g, 0.33mol) dropwise, and react at the same temperature for 2 hours. After the reaction is complete, filter, and concentrate the filtrate to dryness under reduced pressure, add 200mL water and 200mL ethyl acetate, extract and separate layers, wash the organic layer with 100mL saturated brine, concentrate under reduced pressure to dryness, and refine with ethanol to obtain 4-(nitrate phenyl)-3-morpholinone (57.9 g), yield 87%, purity 99.5%.

[0050] 1H-NMR (CDCl3, 300MHz): δ8.31(d, 2H), 6.86(d, 2H), 4.31(s, 1H), 3.52–3.55(m, 3H)

[0051] The chromatographic conditions are:

[0052] Column: Huapu C18, 4.6×250mm, 5μm

[0053]Mobile phase: acetonitril...

Embodiment 2

[0057] Example 2: Preparation of 4-(nitrophenyl)-3-morpholinone

[0058] In a 1000mL reaction flask, p-fluoronitrobenzene (42.3g, 0.3mol) and potassium carbonate (144.9g, 1.05mol) were heated to 60°C in 500mL of acetonitrile, and ethanolamine (20.2g, 0.33mol) was added dropwise to react 18 Hour. Cool down to 0°C, add chloroacetyl chloride (37.3g, 0.33mol) dropwise, and react at the same temperature for 2 hours. After the reaction is complete, filter, and concentrate the filtrate to dryness under reduced pressure, add 200mL water and 200mL ethyl acetate, extract and separate layers, wash the organic layer with 100mL saturated brine, concentrate under reduced pressure to dryness, and refine with ethanol to obtain 4-(nitrate phenyl)-3-morpholinone (53.3 g), yield 80%, purity 99.5%.

Embodiment 3

[0059] Embodiment 3: Preparation of 4-(nitrophenyl)-3-morpholinone

[0060] In a 1000mL reaction flask, p-bromonitrobenzene (60.6g, 0.3mol) and potassium carbonate (144.9g, 1.05mol) were heated to 60°C in 500mL of acetonitrile, and ethanolamine (20.2g, 0.33mol) was added dropwise to react 4 Hour. Cool down to 0°C, add chloroacetyl chloride (37.3g, 0.33mol) dropwise, and react at the same temperature for 2 hours. After the reaction is complete, filter, and concentrate the filtrate to dryness under reduced pressure, add 200mL water and 200mL ethyl acetate, extract and separate layers, wash the organic layer with 100mL saturated brine, concentrate under reduced pressure to dryness, and refine with ethanol to obtain 4-(nitrate phenyl)-3-morpholinone (56.6g), yield 85%, purity 99.5%.

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Abstract

The invention relates to the technical field of preparation of rivaroxaban and an intermediate thereof and particularly relates to a preparation method of 4-(nitrobenzophenone)-3-morpholone which is prepared from halogenated nitrobenzene, ethanolamine and chloroacetyl chloride through a one-pot method. The method for preparing rivaroxaban comprises the steps of reducing 4-(nitrobenzophenone)-3-morpholone into 4-(aminophenyl)-3-morpholone; enabling 4-(aminophenyl)-3-morpholone to react with R-epichlorohydrin to obtain a product; enabling the product to react with N, N-carbonyldiimidazole to obtain a product; enabling the product to react with tert-butyl iminodicarboxylate; preparing hydrochloride; enabling hydrochloride to react with 5-penphene-2-carbonyl chloride. The preparation method of 4-(nitrobenzophenone)-3-morpholone is capable of realizing one-pot production and free of purifying intermediate products in the process, so that the operation process is simplified, the time is saved, and the labor cost is reduced; the preparation method of 4-(nitrobenzophenone)-3-morpholone is low in raw material price, high in obtained product yield and easy to realize large-scale industrial production; in addition, the method for preparing rivaroxaban is cheap, nontoxic and harmless in raw material, simple in process and high in product yield.

Description

technical field [0001] The present invention relates to the technical field of preparation of rivaroxaban and its intermediates, in particular to a preparation method of 4-(nitrophenyl)-3-morpholinone, and also relates to the use of prepared 4-(nitrophenyl) Base) -3-morpholinone to the method for preparing rivaroxaban. Background technique [0002] Rivaroxaban (English name: Rivaroxaban, trade name: Xarelto), chemical name: 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholinone) -4-yl)phenyl)-1,3-oxazolin-5-yl)methyl)thiophene-2-carboxamide, CAS number: 366789-02-8, which is an oral antithrombotic drug developed by Bayer , was approved for marketing in Canada and the EU on September 15, 2008 and October 1, 2008, respectively. The U.S. market was developed by Johnson & Johnson, and it was launched in the U.S. in 2011. In China, Rivaroxaban was officially launched on June 18, 2009 under the product name Xarelto. The structural formula is shown in I. [0003] [0004] Rivaro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/32C07D413/14
CPCC07D265/32C07D413/14
Inventor 范明伟耿凤娈
Owner 山东康美乐医药科技有限公司
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