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Lidiastan related compounds and their preparation methods and uses

A compound and concentrate technology, applied in the field of rivaroxaban-related compounds and their preparation and application, can solve problems such as failure to effectively control and failure to establish a comprehensive and reliable quality control system for rivaroxaban

Active Publication Date: 2021-01-19
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, a comprehensive and reliable quality control system has not been established for rivaroxaban, one of the important reasons is that it has not been able to fully and effectively control its related substances

Method used

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  • Lidiastan related compounds and their preparation methods and uses
  • Lidiastan related compounds and their preparation methods and uses
  • Lidiastan related compounds and their preparation methods and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]

[0044] Add absolute ethanol (90 mL) and compound 1 (20 g) into the reaction flask, heat to 80° C., stir continuously for 30 h, and concentrate to dryness to obtain a concentrate. The concentrate was subjected to silica gel column chromatography (mobile phase dichloromethane:methanol=100:1), and 2.8 g of the compound of formula (II) was obtained by isolation (yield 11.4%).

[0045] The detection spectrum of the compound of formula (II) is as follows.

[0046] 1 H NMR (600MHz, DMSO-d 6 ):δ7.82-7.87(m,4H),5.08(d,1H),3.90-3.92(m,1H),3.55-3.62(m,2H),3.31-3.41(m,4H),1.01(t ,3H); MS(m / z):250.1[M+H] + .

Embodiment 2

[0048]

[0049] Put the compound of formula (II) (1g), 40% methylamine aqueous solution (0.85g) and absolute ethanol (8mL) into the reaction flask, react at 65°C for 3h and then cool down to room temperature, add 16% dilute hydrochloric acid to the reaction solution (2mL), crystallized at 0°C for 3h, then suction filtered, and concentrated the mother liquor to dryness to obtain a concentrate. Add purified water (5 mL), ethyl acetate (5 mL) and triethylamine (0.7 g) to the concentrate, add 5-chlorothiophene-2-formyl chloride (0.6 g) dropwise at room temperature, and stir at room temperature for 1 h after the addition , and then raised to 60 ° C for 1 h. The phases were separated, the organic phase was collected, and concentrated to dryness to obtain a concentrate. The concentrate was separated by silica gel column chromatography (mobile phase dichloromethane:methanol=100:1), and 0.3 g of the compound of formula (I) was obtained (purity 94%, yield 28.4%).

[0050] The detec...

Embodiment 3

[0054]

[0055] The compound of formula (IV) (0.8 g) was added to ammonia solution in methanol (7 M, 23 mL), stirred at room temperature for 15 h, and concentrated to dryness under reduced pressure to obtain a concentrate. Add purified water (11 mL), ethyl acetate (11 mL) and triethylamine (1.5 g) to the concentrate, add 5-chlorothiophene-2-formyl chloride (1.3 g) dropwise at room temperature, and stir at room temperature for 1 h after the addition , and then raised to 60 ° C for 1 h. The phases were separated, the organic phase was collected, and concentrated to dryness to obtain a concentrate. The concentrate was subjected to silica gel column chromatography (mobile phase dichloromethane:methanol=100:1), and 1.7 g of the compound of formula (I) was obtained (yield 81.0%).

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PUM

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Abstract

Disclosed are a rivaroxaban-related compound, and a preparation method and application thereof. The rivaroxaban-related compound is a compound of the formula (I). The compound of the formula (I) can be used as a standard substance (reference substance) for related substances in rivaroxaban, and is applied to quality control of rivaroxaban bulk drugs or preparations.

Description

technical field [0001] The present invention relates to related compounds of rivaroxaban, their preparation method and application. Background technique [0002] Rivaroxaban (chemical name: 5-chloro-nitrogen-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine -5-yl}methyl)-2-thiophene-carboxamide) is an anticoagulant drug developed by Bayer HealthCare Co., Ltd. in Germany. It was approved by the FDA in July 2011 and listed in the United States. It is used for elective hip or Adult patients undergoing knee replacement surgery to prevent venous thrombosis (VTE). Rivaroxaban is an oral, highly bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require cofactors (such as antithrombin III) for its activity. Activation of factor X to factor Xa (FXa) through intrinsic and extrinsic pathways plays an important role in the blood coagulation cascade. [0003] Safety, effectiveness and quality controllability are three impor...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/38G01N30/02
CPCC07D333/38G01N30/02G01N2030/027
Inventor 孙晓伟张倩如杨路张红芬陈尧刘峰张园园
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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