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Method for preparing rivaroxaban midbody 4-(4-aminophenyl)-3-morpholone

A technology of aminophenyl and rivaroxaban is applied in the preparation of rivaroxaban intermediate 4--3-morpholinone, in the field of rivaroxaban intermediate, and can solve the problem of low yield and severe reaction conditions and other problems, to achieve the effect of low raw material cost, simple process route and high yield

Inactive Publication Date: 2015-08-12
ZHEJIANG TIANSHUN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing several synthetic routes of 4-(4-aminophenyl)-3-morpholinone have problems such as low yield or severe reaction conditions.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Preparation of phenylaminoethanol

[0027] Add 15mL of acetone to the round bottom flask, then add 20mL of aniline, stir slowly and fully dissolve, then add 10mL of ethylene oxide, stir and react in an ice bath to generate phenylaminoethanol; add a small amount of ethyl acetate after 15h of reaction Extract, combine the organic phases, add anhydrous sodium sulfate to dry, distill under reduced pressure, and separate by column chromatography to obtain phenylaminoethanol with a yield of 82%.

Embodiment 2

[0029] Preparation of 4-phenyl-3-morpholinone

[0030] Add 1g of phenylaminoethanol and 0.834g of potassium tert-butoxide into a three-necked flask, then add 10mL of anhydrous tetrahydrofuran as a solvent, under the protection of nitrogen, fully stir and dissolve in an oil bath, the temperature of the oil bath is 38°C, and then add 1mL of chloroacetic acid Ethyl ester, continue to react for 16h to obtain 4-phenyl-3-morpholinone. After the reaction is over, spin out the solvent tetrahydrofuran with a rotary evaporator, then add a small amount of ethyl acetate for extraction and separation, combine the organic phases, add anhydrous sodium sulfate to dry, distill under reduced pressure, and separate by column chromatography, add petroleum ether for recrystallization 4-Phenyl-3-morpholinone is obtained. The yield was 83%.

Embodiment 3

[0032] Preparation of 4-(4-nitrophenyl)-3-morpholinone

[0033] Add 0.177g of 4-phenyl-3-morpholinone into a round bottom flask, add 2.8mL 50mmol of 98% concentrated sulfuric acid, stir to dissolve, then slowly add 0.1mL 14mol of 65% concentrated nitric acid under ice bath, and continue stirring for 2h , to give 4-(4-aminophenyl)-3-morpholinone. After the reaction, add 15 mL of water to the reaction vessel, and drop a small amount of ammonia water to adjust the pH value to neutral, a large amount of precipitates are formed, which are filtered by suction, washed, dried and recrystallized with acetone to obtain 4-(4-nitrophenyl)- 3-morpholinone. The yield is 81%

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PUM

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Abstract

The invention provides a method for preparing a rivaroxaban midbody 4-(4-aminophenyl)-3-morpholone. The method comprises the following steps: adding aniline into ethylene oxide so as to generate phenylamino ethanol; further adding ethyl chloroacetate to continuously react to obtain 4-phenyl-3-morpholone; firstly adding concentrated sulfuric acid, slowly adding concentrated nitric acid in an ice bath to react to obtain 4-(4-aminophenyl)-3-morpholone, wherein the volume ratio of concentrated sulfuric acid to concentrated nitric acid is (25-30):1; and adding palladium carbon for reducing so as to obtain the rivaroxaban midbody 4-(4-aminophenyl)-3-morpholone. The method is simple in process route, and is gentle in reaction, low in raw material cost and high in yield after condition optimization.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a rivaroxaban intermediate, in particular to a preparation method of the rivaroxaban intermediate 4-(4-aminophenyl)-3-morpholinone. Background technique [0002] Rivaroxaban is a new type of anticoagulant that can be directly taken orally. It directly inhibits the activated blood coagulation factor Xa, has an exact anticoagulant effect, does not require continuous monitoring, and has high safety. On September 15, 2008 and October 1, 2008, rivaroxaban was approved for marketing in Canada and the European Union respectively, and the trade name was Xarelto. On July 1, 2011, Bayer and Johnson & Johnson jointly announced that the anticoagulant drug rivaroxaban (English common name: Rivaroxaban, Chinese product name: Xarelto, English trade name: Xarelto) has been approved by the FDA for the prevention of Deep Vein Thrombosis (DVT). On November 4, 2011, rivaroxaban was approved by the...

Claims

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Application Information

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IPC IPC(8): C07D265/32
CPCC07D265/32
Inventor 张胜
Owner ZHEJIANG TIANSHUN BIOTECH