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Rivaroxaban preparation method

A technology of rivaroxaban and morpholinone, which is applied in the field of preparation of rivaroxaban, can solve the problems of severe reaction conditions and low yield, and achieve the effect of low raw material cost, simple steps and optimized conditions

Active Publication Date: 2015-08-26
ZHEJIANG TIANSHUN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

, the current synthesis route of rivaroxaban has problems such as low yield or severe reaction conditions

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of phenylaminoethanol

[0033] 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

[0035] Preparation of 4-phenyl-3-morpholinone

[0036] 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

[0038] Preparation of 4-(4-nitrophenyl)-3-morpholinone

[0039] 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, 15 mL of water was added to the reaction vessel, and a small amount of ammonia water was added dropwise to adjust the pH value to neutral, and a large amount of precipitate was generated, which was filtered by suction, washed, dried, and recrystallized with acetone to obtain 4-(4-aminophenyl)-3 - Morpholinone. The yield is 81%

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PUM

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Abstract

The invention provides a rivaroxaban preparation method. 4-(4-aminophenyl)-3-molindone and (S)-N-glycidyl phthalimide are reacted to form 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholine-4-yl) phenyl)-1,3-oxazoline-5-yl) methyl) thiophene-2-formamide, wherein the rivaroxaban preparation method comprises the steps: adding ethylene oxide to phenylamine to generate hydroxyethyl aniline; adding ethyl chloroacetate and continuously reacting to obtain 4-phenyl-3-molindone; adding concentrated sulfuric acid, slowly adding concentrated nitric acid under an ice bath, wherein the volume ratio of the concentrated sulfuric acid and the concentrated nitric acid is (25-30): 1; reacting to obtain the 4-(4-aminophenyl)-3-molindone; adding palladium carbon to carry out reduction reaction, thereby obtaining rivaroxaban intermediates, i.e., 4-(4-aminophenyl)-3-molindone. The rivaroxaban preparation method provided by the invention has a simple processing route; after conditions are optimized, reaction is mild, cost of raw materials is low and yielding is high.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of rivaroxaban. 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 US FDA for the prevention of stroke or systemic embolism in patients with non-valvular atrial ...

Claims

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Application Information

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IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 张胜
Owner ZHEJIANG TIANSHUN BIOTECH
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