Method for synthesizing rivaroxaban process impurity

A technology of process impurities, rivaroxaban, applied in the direction of organic chemistry, etc., to achieve the effects of easy availability of raw materials, simple operation and enhanced control

Inactive Publication Date: 2018-06-15
江苏悦兴医药技术有限公司
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  • Abstract
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  • Claims
  • Application Information

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After searching, there is no bibliographical report about the synthesis of this impurity, therefore, it has impor

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  • Method for synthesizing rivaroxaban process impurity
  • Method for synthesizing rivaroxaban process impurity
  • Method for synthesizing rivaroxaban process impurity

Examples

Experimental program
Comparison scheme
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Example Embodiment

[0014] Example one:

[0015] 2-[(2R)-2-hydroxy-3-[[4-(3-oxo-4-morpholine)phenyl]amino]propyl]-1H-isoindole-1,3(2H)- Preparation of diketone (4)

[0016]

[0017] Add 4-(4-aminophenyl)morpholin-3-one (192.2g, 1mol), 2-(2-chloroethoxy)propane (203.2g, 1mol), and 790ml of ethanol into a 1000ml three-necked flask and start After stirring, the temperature was raised to reflux, and TLC was detected. It was found that the raw material disappeared after 10 hours of reaction, and the reaction was completed and the temperature was reduced to room temperature. Suction filtration, washing with 100 ml of ethanol for three times, drying to obtain a total of 363.78 g of the compound (4), with a yield of 92%, 98.67% by HPLC.

[0018] 1 HNMR (600MHz, DMSO-d6, δppm): 7.90-7.76 (m, 4H), 7.04 (d, 2H), 6.62 (d, 2H), 5.67 (t, 1H), 5.20 (d, 1H), 4.20 ( s, 2H), 4.10-3.85 (m, 3H), 3.71-3.55 (m, 4H), 3.28-2.90 (m, 2H);

Example Embodiment

[0019] Embodiment two:

[0020] (S)-4-(4-((3-amino-2-hydroxypropyl)aminophenyl)morpholin-3-one hydrochloride (5)

[0021]

[0022] Add 2-[(2R)-2-hydroxy-3-[[4-(3-oxo-4-morpholine)phenyl]amino]propyl]-1H-isoindole-1 to a 2000ml three-necked flask ,3(2H)-dione (360g, 0.910mol), 30% methylamine solution 377g and 1440ml ethanol were stirred, heated to 65°C, reacted for 8h, TLC detected that the reaction ended. Add 25% HCl solution to adjust PH=4-5. Rotate and evaporate to dryness, add 700 ml of ethanol for 2 hours at room temperature to be slurried, filter with suction, and wash with 200 ml of ethanol three times. The dried compound (5) is 242.37 g in total and the yield is 88.26%. HPLC detected 99.24%.

[0023] 1 HNMR (600MHz, DMSO-d6, δppm): 7.60 (d, 2H), 7.42 (d, 2H), 5.69 (t, 1H), 5.24 (d, 1H), 4.68-4.59 (m, 1H), 4.20 ( s, 2H), 4.18(t, 1H), 3.95(d, 2H), 3.89(d, 1H), 3.75(d, 2H), 2.94-2.78(m, 2H), 1.77-1.65(s, 2H) ;

Example Embodiment

[0024] Embodiment three:

[0025] (S)-5-chloro-N-(3-(5-chlorothiophen-2-carboxamido)-2-hydroxypropyl)-N-(4-(3-oxomorpholino)phenyl) Preparation of thiophene-2-carboxamide

[0026]

[0027] Add (S)-4-(4-((3-amino-2-hydroxypropyl)aminophenyl)morpholin-3-one hydrochloride (5) (240g, 0.795mol) to a 3000ml three-necked flask, Triethylamine (321.78g, 3.18mol), 1400ml of dichloromethane, stir, stir in an ice bath, weigh out 5-chloro-2-acylchlorothiophene (359g, 1.99mol) solution in 600ml of dichloromethane and add dropwise to the reaction flask Stir in an ice bath for 2h, react at room temperature for 4h, and TLC detects the end of the reaction. Add 600ml of water, stir and precipitate a solid, filter with suction, wash with 100ml of dichloromethane for three times, dry to obtain 377.46g, yield 85.63%, HPLC detection 98.95% .

[0028] 1 HNMR (600MHz, DMSO-d6, δppm): 8.96 (t, 1H), 8.64 (t, 1H), 7.85 (d, 1H), 7.74 (d, 1H), 7.56 (d, 2H), 7.42 (d, 2H), 7.21(d, 1H), 5.55(d, 1H), 4.95-4.77(m,...

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Abstract

The invention discloses a method for synthesizing a rivaroxaban process impurity, and belongs to the technical field of chemical pharmacy. The method comprises the following steps: preparing 2-[(2R)-2-hydroxy-3-[[4-(3-oxo-4-morpholin)phenyl]amino]propyl]-1H-isoindole-1,3(2H)-dione (4) from 4-(4-aminophenyl)morpholin-3-one (2) and (S)-N-glycidyl phthalimide (3); hydrolyzing the compound (4), and salifying the hydrolyzed compound (4) to generate (S)-4-(4-((3-amino-2-hydroxypropyl)aminophenyl)morpholin-3-one hydrochloride (5); and preparing (S)-5-chloro-N-(3-(5-chlorothienyl-2-formamido)-2-hydroxypropyl)-N-(4-(3-oxomorpholino)phenyl)thiophene-2-carboxamide (1) from the compound (5) and 5-chlorothiophene-2-carbonyl chloride (6). The highly-pure rivaroxaban impurity synthesized in the inventioncan be used s an impurity standard product in the detection and analysis of a rivaroxaban finished product, so the accurate localization and qualitative diagnosis of the impurity in the detection andanalysis of the rivaroxaban finished product are improved, and the enhancement of the control of the impurity is benefited, thereby the quality of the rivaroxaban finished product is improved. The method has the advantages of cheap and easily available raw materials, and simplicity in operation, and allows the yield of the obtained product to be (70 +/- 5)% and the HPLC purity of the product to be equal to or more than 98%.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, in particular to a rivaroxaban process impurity (S)-5-chloro-N-(3-(5-chlorothiophene-2-carboxamido)-2-hydroxypropyl) -N-(4-(3-oxomorpholino) phenyl) thiophene-2-carboxamide synthetic method. Background technique [0002] Rivaroxaban is an oral, bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (eg, antithrombin III) for activity. Activation of factor X to factor Xa (FXa) through intrinsic and extrinsic pathways plays an important role in the blood coagulation cascade. Rivaroxaban was developed by Johnson & Johnson and Bayer. It was launched in the European Union and Canada in 2008. It was officially launched in China in June 2009. It was launched in the United States on July 1, 2011. Up to now, Xarelto has been sold in more than 50 countries around the world. countries listed. [0003] The chemical name of rivaroxaba...

Claims

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Application Information

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IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 花海堂翟富民郑剑波包华兰石文革
Owner 江苏悦兴医药技术有限公司
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