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Detection and preparation methods of azilsartan medoxomil impurities

A technology of azilsartan medoxomil and a detection method is applied in the detection and preparation field of azilsartan medoxomil tetramer impurities, can solve the problems such as impurity confirmation and synthesis method that have not been reported in literature, and achieves the effect of simple operation

Active Publication Date: 2015-01-28
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Adopt this method to prepare azilsartan medoxomil, the HPLC purity is only about 97.6%, wherein the content (HPLC peak area) of a kind of impurity exceeds 1.0%, is generally about 3.0%, does not yet have the confirmation and synthetic method of this impurity of document report at present

Method used

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  • Detection and preparation methods of azilsartan medoxomil impurities
  • Detection and preparation methods of azilsartan medoxomil impurities
  • Detection and preparation methods of azilsartan medoxomil impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1 prepares azilsartan medoxomil

[0041] At 10°C, add azilsartan (8.4g), DMAc (40ml), DMAP (0.5g), TsCl (3.9g), 4-hydroxymethyl-5-methyl-1,3 - After dioxol-2-one (2.4g) was stirred and dissolved, potassium carbonate (2.6g) was added, and after stirring for 3 hours, 0.3N HCl was added dropwise to the reaction solution to adjust the pH to 5, and added dropwise 50ml of acetone / water (1:1), precipitated a large amount of solids, kept warm for 1h, filtered to obtain a wet product, then added acetone (20ml) to make a slurry, filtered, and vacuum dried at 50°C for 10h to obtain 1.8g of azilsartan medoxomil, HPLC purity 96.8% .

Embodiment 2L

[0042] Embodiment 2LC-MS detection method

[0043] The azilsartan medoxomil prepared in Example 1 was dissolved in the diluent DMF,

[0044] Chromatographic column: Agilent Eclipse XDB C184.6x 250mm, 5um;

[0045] Mobile phase: A phase: 10Mm ammonium acetate buffer salt (pH3.5), B phase: acetonitrile;

[0046] Column temperature: 30°C;

[0047] Running time: 60min, post-running time: 8min;

[0048] Elution gradient:

[0049] Time(min)

A％

B％

0

55

45

8

55

45

18

40

60

28

10

90

60

10

90

[0050] The detector is a quadrupole time-of-flight mass spectrometer (Q-TOF).

[0051]ESI positive polarity, automatic MS / MS mode; Capillary voltage: 3.5Kv; Nebulizer pressure: 45psi; Dry gas (nitrogen) flow rate: 12L / min;

[0052] Drying gas temperature: 350°C.

[0053] Q-TOF full scan results show that m / z1753.5375 and m / z1791.4935 have unknown impurities [M+H] + Ions and [M+K] + ions, in...

Embodiment 3

[0054] Embodiment 3: the synthesis of azilsartan tetramer impurity

[0055] At 10°C, Azilsartan (8.4g), DMAc (50ml), DMAP (0.5g), TsCl (3.9g) were added successively to the reaction vessel and stirred to dissolve, then triethylamine (6.5g) was slowly added dropwise, After insulated and stirred for 3 hours, 0.3N HCl was added dropwise to the reaction solution to adjust the pH to 4-6. Add 50ml of acetone / water (1:1) dropwise, a large amount of solids precipitate out, keep warm for 1h, filter to obtain a wet product, then add acetone (20ml) for slurry, filter, and vacuum dry at 50°C for 10h to obtain 5.6g of pure tetramer (HPLC purity : 99.75%), retention time: 38.36min, relative retention time: 2.24min.

[0056] The target unknown impurity prepared is subjected to NMR experiment:

[0057] Instrument: Bruker AVANCE AV 400 superconducting pulse Fourier transform nuclear magnetic resonance spectrometer,

[0058] Analysis method: JY / T 007-1996 Superconducting Pulse Fourier Transf...

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Abstract

The invention relates to detection and preparation methods of azilsartan medoxomil tetramer impurities. The detection method comprises the step of performing gradient elution by using an Agilent Eclipse XDB C18 chromatographic column and a mixed mobile phase formed by ammonium acetate buffer salt with the pH value of 3.5 as a mobile phase A and acetonitrile as a mobile phase B according to the following conditions: the volume ratio of the mobile phase A to the mobile phase B from 0 to 8min is 55:45, the volume ratio of the mobile phase A to the mobile phase B from 8min to 18min is 55:45 to 40:60, the volume of the mobile phase A to the mobile phase B from 18min to 28min is 40:60 to 10:90, and the volume ratio of the mobile phase A to the mobile phase B from 28min to 60min is 10:90; and a detector is a quadrupole time of flight mass spectrometry detector (Q-TOF).

Description

technical field [0001] The invention belongs to the technical field of organic and pharmaceutical synthesis, and in particular relates to the detection and preparation method of azilsartan medoxomil tetramer impurities. Background technique [0002] Azilsartan medoxomil, also known as (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2' -(5-Oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate , angiotensin II receptor antagonists (ARBs) developed by Japan's Takeda Pharmaceutical Co., Ltd. are prodrugs of azilsartan (azilsartan) for the treatment of hypertension; the structure of azilsartan medoxomil is shown in formula (I) Shown: [0003] [0004] On February 25, 2011, the US FDA approved azilsartan medoxomil potassium (trade name Edarbi) for the treatment of hypertension in adults, and clinical studies have confirmed that it has a stable and long-lasting antihypertensive effect. [0005] Clinical research data show that compared ...

Claims

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Application Information

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IPC IPC(8): G01N30/02G01N30/06C07D498/22
Inventor 雷鑫王功金
Owner SUNSHINE LAKE PHARM CO LTD
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