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Preparation method of Rivaroxaban

A technology of rivaroxaban and aminomethyl, applied in the field of preparation of rivaroxaban, can solve the problems of unsuitable industrial production of rivaroxaban, difficult recovery of solvents, many reaction steps, etc., and achieves easy product separation and reaction The effect of short steps and less waste

Active Publication Date: 2016-10-12
SHANGHAI PUKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] The current preparation method of rivaroxaban generally has problems such as many reaction steps, complex operation, difficult recovery of solvent, large pollution, low yield, high reaction cost, etc., and is not suitable for industrial production of rivaroxaban

Method used

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  • Preparation method of Rivaroxaban

Examples

Experimental program
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Effect test

Embodiment 1

[0027] A preparation method for rivaroxaban, comprising the following steps: in a 2000ml four-neck flask, add solid (s)-5-aminomethyl-2-oxazolidinone 100g (0.86mol), triethylamine 217g (2.15mol), 800g of dichloromethane, slowly dropwise added 202.7g (1.12mol) of 5-chloro-2-acylchlorothiophene. The temperature was raised to 40°C with stirring, and the reaction was completed after reflux for 6 hours. The reaction solution was directly added to ice water, the organic layer was washed with water, dried, and concentrated to obtain an intermediate: 5-chloro-N-((5S)-2-oxo-1,3-oxazolin-5-yl)methyl) Thiophene-2-carboxamide, light yellow solid 181.6g, yield 81%.

[0028] Add 181.6g (0.7mol) of the intermediate obtained in the previous step into a 1000ml four-necked flask, and throw 358g (1.4mol) of 4-(4-bromophenyl)morpholin-3-one and 26.7g of cuprous iodide (0.14mol), potassium dihydrogenphosphate 23.8g (0.175mol) and 1,4-dioxane 910g. Stir and heat up to 105°C to start heat preserv...

Embodiment 2

[0030] A preparation method for rivaroxaban, comprising the following steps: in a 2000ml four-necked flask, add solid (s)-5-aminomethyl-2-oxazolidinone 100g (0.86mol), pyridine 204g (2.58 mol), dichloromethane 800g, and 202.7g (1.12mol) of 5-chloro-2-acylchlorothiophene were slowly added dropwise. The temperature was raised to 40°C with stirring, and the reaction was completed after reflux for 6 hours. The reaction solution was directly added to ice water, the organic layer was washed with water, dried, and concentrated to obtain an intermediate: 5-chloro-N-((5S)-2-oxo-1,3-oxazolin-5-yl)methyl) Thiophene-2-carboxamide, light yellow solid 185g, yield 82.5%.

[0031] 185g (0.71mol) of the intermediate obtained in the previous step was added in a four-necked flask of 1000ml, and 400g (1.56mol) of 4-(4-bromophenyl) morpholin-3-one was cast, and 27.4g (1.56mol) of cuprous iodide ( 0.144mol), potassium dihydrogen phosphate 24g (0.177mol) and DMF910g. Stir and heat up to 110°C to ...

Embodiment 3

[0033] A preparation method for rivaroxaban, comprising the following steps: in a 2000ml four-necked flask, add solid (s)-5-aminomethyl-2-oxazolidinone 100g (0.86mol), potassium carbonate 356g ( 2.58mol), dichloroethane 800g, and 202.7g (1.12mol) of 5-chloro-2-acylchlorothiophene were slowly added dropwise. The temperature was raised to 60°C with stirring, and the reaction was completed after reflux for 6 hours. The reaction solution was directly added to ice water, the organic layer was washed with water, dried, and concentrated to obtain an intermediate: 5-chloro-N-((5S)-2-oxo-1,3-oxazolin-5-yl)methyl) Thiophene-2-carboxamide, light yellow solid 179g, yield 80%.

[0034] 179g (0.69mol) of the intermediate obtained in the previous step was added to a 1000ml four-necked flask, and 441.6g (1.725mol) of 4-(4-bromophenyl)morpholin-3-one and 19.8g of cuprous bromide were cast (0.138mol), dipotassium hydrogen phosphate 39.5g (0.173mol) and DMF910g. Stir and heat up to 110°C to s...

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Abstract

The invention discloses a preparation method of Rivaroxaban. The method is characterized by comprising steps as follows: S01, (s)-5-aminomethyl-2-oxazolidinone is dissolved in halohydrocarbon, alkali is added, the mixture is evenly stirred, 5-chlorothiophene-2-carbonyl chloride is dropwise added, a condensation reaction is conducted, and an intermediate, namely, 5-chlorothiophene-N-((5S)-2-oxo-1,3-oxazoline-5-yl)methyl)-2-formamide, is obtained through aftertreatment; S02, the intermediate and 4-(4-bromophenyl)morpholin-3-one are taken, a solvent and a catalyst are added for a reaction, and a final product, namely, Rivaroxaban, is prepared. With the preparation method of Rivaroxaban, adopted raw materials and solvent are cheap and easy to obtain, reaction steps are short, the economy is good, reaction conditions are mild, the product is easy to separate, high in purity and high in yield, few three-wastes are produced, few pollutants exist, and industrial production is facilitated.

Description

technical field [0001] The invention relates to a preparation method of rivaroxaban, which belongs to the technical field of drug synthesis. Background technique [0002] The current preparation method of rivaroxaban generally has problems such as many reaction steps, complicated operation, difficult recovery of solvent, large pollution, low yield, high reaction cost, etc., and is not suitable for industrial production of rivaroxaban. Contents of the invention [0003] The technical problem solved by the present invention is to provide a preparation method of rivaroxaban which has simple steps and is suitable for industrial production. [0004] In order to solve the problems of the technologies described above, the technical solution adopted in the present invention is: [0005] A preparation method of rivaroxaban, characterized in that: comprising the following steps: [0006] S01, dissolve (s)-5-aminomethyl-2-oxazolidinone in halogenated hydrocarbon, add alkali, stir e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 李勇刚汪迅夏小波张珍顾波
Owner SHANGHAI PUKANG PHARMA
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