Preparation method of rivaroxaban

A technology of rivaroxaban and compounds, which is applied in the field of medicine, can solve the problems of long synthetic route, complex preparation process, and low total yield, and achieve the effects of mild reaction conditions, simple synthetic route, and high purity of the product

Inactive Publication Date: 2014-09-03
HYBIO PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Two, take 4-(4-aminophenyl)-3-morpholinone as the starting material through condensation, ring closure, after reacting with phthalimide potassium salt, react with methyl chloroformate again to obtain ( S)-methyl 2-hydroxy-3-(1,3-dioxo-isoindolin-2-yl)propyl-4-(3-oxo-morpholine)phenylcarbamate, after condensation, Rivaroxaban is obtained under the acti

Method used

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  • Preparation method of rivaroxaban
  • Preparation method of rivaroxaban
  • Preparation method of rivaroxaban

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preparation example Construction

[0050] A preparation method of rivaroxaban, comprising:

[0051] 1) 4-(4-iodophenyl)-3-morpholinone, (S)-(+)-N-(3-amino-2-hydroxyisopropyl)phthalimide and acid-binding Reagent reaction, obtain the compound with formula (I) structure,

[0052]

[0053] 2) converting the compound having the structure of formula (I) into rivaroxaban.

[0054]According to the present invention, the (S)-(+)-N-(3- Amino-2 hydroxyisopropyl) phthalimide, acid-binding agent mixed reaction, obtain the compound with formula (I) structure; Described acid-binding agent is preferably potassium carbonate, sodium carbonate, pyridine, triethylamine And one or more in DIPEA, more preferably salt of wormwood, sodium carbonate, pyridine, triethylamine or DIPEA, most preferably salt of wormwood; The solvent of described reaction is preferably tetrahydrofuran (THF), dioxane and DMF One or more, more preferably tetrahydrofuran, dioxane or DMF, most preferably tetrahydrofuran; the 4-(4-iodophenyl)-3-morpholinon...

Embodiment 1

[0082] The preparation of formula (I) compound

Embodiment 1-1

[0084] In a 5L three-necked flask, add 4-(4-iodophenyl)-3-morpholinone (30.3g, 100mmol), (S)-(+)-N-(3-amino-2-hydroxyisopropyl Base) phthalimide (24.2g, 110mmol), anhydrous potassium carbonate (13.8g, 100mmol), tetrahydrofuran solution (540ml, 10.0ml / g) were stirred, and the obtained suspension was gradually warmed to 64 ° C, refluxed , clarified, the product slowly precipitated after about 4 hours, kept the reflux reaction for 24 hours, allowed to cool to room temperature, filtered with suction, washed the filter cake with ether 200ml*3 times, sucked dry, and sent it to 45°C for 6 hours to obtain the formula (I) The compound of structure-g, the yield is 85.5%.

[0085] The compound of the formula (I) structure is detected by high performance liquid chromatography, and the results can be found in figure 1 , figure 1 It is the high-performance liquid chromatogram of the compound of the formula (I) structure described in Example 1-1, and the results show that its purity is 99....

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Abstract

The invention provides a preparation method of rivaroxaban, which uses 4-(4-iodophenyl)-3-morpholone and (S)-(+)-N-(3-amino-2-hydroxyisopropyl)phthalimide as initial raw materials. The synthesis route is simple, the reaction conditions in each reaction are mild, and the product is easy to separate; and thus, the reaction yield is high, the product purity is high, and the method can be used for industrial production.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of rivaroxaban. Background technique [0002] Rivaroxaban, the English common name is rivaroxaban, the Chinese product name is Xarelto, and the English product name is Xarelto. It was developed by the German Bayer Pharmaceutical Company and has been approved by the FDA for the prevention of deep vein thrombosis (DVT); Shaban is the first approved factor Xa inhibitor. By inhibiting factor Xa, it can interrupt the intrinsic and extrinsic pathways of the coagulation cascade, inhibit the generation of thrombin and thrombus formation, and can be used to prevent deep venous thrombosis, acute Coronary artery syndrome and stroke prevention, currently, rivaroxaban and dabigatran etexilate are considered to be the most promising antithrombotic drugs in the future. [0003] At present, the synthetic methods of rivaroxaban reported in the literature have the following three cate...

Claims

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Application Information

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IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 袁慧星肖庆李国弢马亚平袁建成
Owner HYBIO PHARMA
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