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Preparation method of 4-(4-amino phenyl)-3-morpholone and intermediate of 4-(4-amino phenyl)-3-morpholone

An aminophenyl and intermediate technology, applied in the field of preparation of 4-(4-aminophenyl)-3-morpholinone, can solve the problem of high raw material prices

Active Publication Date: 2014-05-21
HUBEI XUNDA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are two steps in this route, the yield is higher, but the raw materials involved are also expensive

Method used

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  • Preparation method of 4-(4-amino phenyl)-3-morpholone and intermediate of 4-(4-amino phenyl)-3-morpholone
  • Preparation method of 4-(4-amino phenyl)-3-morpholone and intermediate of 4-(4-amino phenyl)-3-morpholone
  • Preparation method of 4-(4-amino phenyl)-3-morpholone and intermediate of 4-(4-amino phenyl)-3-morpholone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Preparation of 2-(2-chloroethoxy)-N-phenyl-acetamide

[0042] Add 93g (1mol) of aniline, 1000ml of dichloromethane, and 112g (1.1mol) of triethylamine into the reaction kettle, cool in an ice bath to 0°C, and dropwise add 157g (1mol) of 2-(2-chloroethoxy) acetyl chloride ), stirring at 25°C for 4 hours, adding 200ml of water, separating, washing with water, drying with anhydrous sodium sulfate, filtering, and recovering under reduced pressure to dryness to obtain 205g of brown oil, with a yield of 96%.

[0043] Preparation of 4-phenyl-3-morpholinone

[0044] Add 106g (0.5mol) of 2-(2-chloroethoxy)-N-phenylacetamide, 800ml of DMF, and 138g (1mol) of potassium carbonate into the reaction kettle, heat at 100°C for 8h, cool, add 4000ml of water, and filter , washed with water, and dried to obtain 69 g of a yellow-white solid, with a yield of 78%.

[0045] Preparation of 4-(4-nitrophenyl)-3-morpholinone

[0046] Add 177g (1mol) of 4-phenyl-3-morpholinone and 1200ml of ace...

Embodiment 2

[0050] Preparation of 2-(2-((phenylsulfonyl)oxy)ethoxy)-N-phenyl-acetamide

[0051] Add 93g (1mol) of aniline, 1000ml of dichloromethane, and 101g (1mol) of triethylamine into the reaction kettle, cool in an ice bath to 0°C, add 2-(2-((benzenesulfonyl)oxy)ethoxy ) Acetyl chloride 278g (1mol), after dropping, stirred at 0-5°C for 4h, added 200ml of water, separated, washed with water, dried over anhydrous sodium sulfate, filtered, recovered under reduced pressure to dryness to obtain 291g of brown oil, with a yield of 87%.

[0052] Preparation of 4-phenyl-3-morpholinone

[0053] Add 167.5g (0.5mol) of 2-(2-((phenylsulfonyl)oxy)ethoxy)-N-phenyl-acetamide, 800ml of DMF, and 138g (1mol) of potassium carbonate into the reaction kettle, heat for 100 React at ℃ for 8 hours, cool, add 4000ml of water, filter, wash with water, and dry to obtain 71g of yellow-white solid with a yield of 81%.

[0054] Preparation of 4-(4-nitrophenyl)-3-morpholinone

[0055] Add 177g (1mol) of 4-phenyl...

Embodiment 3

[0059] Preparation of 2-(2-((methylsulfonyl)oxy)ethoxy)-N-phenyl-acetamide

[0060] 93g (1mol) of aniline, 1000ml of methyl tert-butyl ether, and 101g (1mol) of triethylamine were added to the reaction kettle, cooled to 0°C in an ice bath, and 2-(2-((methylsulfonyl)oxy) was added dropwise Ethoxy) acetyl chloride 216g (1mol), after dropping, stir at 0-5°C for 4h, add 200ml of water, separate liquid, wash with water, dry with anhydrous sodium sulfate, filter, recover under reduced pressure to dryness to obtain 207g of brown oil, yield 76%.

[0061] Preparation of 4-phenyl-3-morpholinone

[0062] Add 136.5g (0.5mol) of 2-(2-((methylsulfonyl)oxy)ethoxy)-N-phenyl-acetamide, 800ml of DMF, and 138g (1mol) of potassium carbonate into the reaction kettle, heat for 100 React at ℃ for 8 hours, cool, add 4000ml of water, filter, wash with water, and dry to obtain 75g of yellow-white solid with a yield of 85%.

[0063] Preparation of 4-(4-nitrophenyl)-3-morpholinone

[0064] Add 177g (...

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Abstract

The invention belongs to the technical field of preparing 4-(4-amino phenyl)-3-morpholone, especially relates to a preparation method of 4-(4-amino phenyl)-3-morpholone and intermediate of the 4-(4-amino phenyl)-3-morpholone. The method comprises the following steps: amide intermediate cyclization, nitration, and reduction. The raw material aniline is a low-cost chemical, and the acylation raw material is easy to synthetize and low in cost. Compared with documents in which acylation is directly carried out after nitration, in the method disclosed by the invention, nitration is carried out after acylation, so that the method disclosed by the invention has the advantages no substituted group protection, high selectivity, less steps, high yield and the like. The preparation process does not need harsh reaction conditions such as high pressure, high temperature and deep cooling and also does not need an expensive palladium-carbon catalyst, and meets the requirements of industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation of 4-(4-aminophenyl)-3-morpholinone, in particular to a new preparation method of 4-(4-aminophenyl)-3-morpholinone and the preparation method intermediate. Background technique [0002] The chemical structure of 4-(4-aminophenyl)-3-morpholinone is as follows [0003] [0004] 4-(4-Aminophenyl)-3-morpholinone is a key intermediate in the synthesis of a new anticoagulant rivaroxaban [0005] It is reported in the literature that there are many synthetic routes of 4-(4-aminophenyl)-3-morpholinone, and those that can be industrialized or have industrial application value mainly contain the following routes [0006] 1) Werner equals the article published in Bioorganic & Medicinal Chemistry Letters in 2004 [0007] Chlorothiophenecarboxamides as P1surrogates of inhibitors of blood coagulation factor Xa [0008] [0009] N-(2-chloroethoxy)acetyl p-nitroaniline is cyclized under the action o...

Claims

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Application Information

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IPC IPC(8): C07C235/16C07C231/02C07C59/135C07C309/73C07C309/66C07C303/30C07D265/32
Inventor 叶刚赵玲李亮
Owner HUBEI XUNDA PHARMA
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