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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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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

After searching, there is no bibliographical report about the synthesis of this impurity, therefore, it has important practical significance to provide a synthetic method of rivaroxaban for the preparation of impurity standard

Method used

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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
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Effect test

Embodiment 1

[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 ethanol to a 1000ml three-necked flask, and start Stir, heat up to reflux, point TLC detection, it is found that the raw material disappears after 10 hours of reaction, the reaction is completed, and the temperature is lowered to room temperature. Suction filtration, washing with 100 ml of ethanol three times, and drying to obtain 363.78 g of the compound (4) with a yield of 92% and a detection rate of 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);

Embodiment 2

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

[0021]

[0022] Add 2-[(2R)-2-hydroxyl-3-[[4-(3-oxo-4-morpholine)phenyl]amino]propyl]-1H-isoindole-1 into a 2000ml three-necked flask , 3(2H)-diketone (360g, 0.910mol), 30% methylamine solution 377g and 1440ml ethanol were stirred, the temperature was raised to 65°C, and the reaction was carried out for 8h, and the reaction was detected by TLC. Add 25% HCl solution to adjust pH=4-5. Rotary evaporate to dryness, add 700ml of ethanol to beat at room temperature for 2 hours, filter with suction, wash with 200ml of ethanol three times, and dry the compound (5) in a total of 242.37g with a yield of 88.26%. HPLC detection 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) ;

Embodiment 3

[0025] (S)-5-chloro-N-(3-(5-chlorothiophene-2-formylamino)-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) into a 3000ml three-necked flask, Stir triethylamine (321.78g, 3.18mol), dichloromethane 1400ml, stir in an ice bath, weigh 5-chloro-2-acylchlorothiophene (359g, 1.99mol) solution in 600ml dichloromethane, add dropwise to the reaction flask , stirred in an ice bath for 2 hours, reacted at room temperature for 4 hours, and the reaction was detected by TLC. Added 600ml of water, stirred to have solid precipitation, suction filtered, washed three times with 100ml of dichloromethane, dried to obtain 377.46g, yield 85.63%, HPLC detected 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, 1H), 4.25-4.14...

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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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