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HPLC analysis method of key intermediate impurities for dipyridamole synthesis

An analytical method and dipyridamole technology are applied in the field of HPLC analysis of key intermediate impurities in the synthesis of dipyridamole, and achieve the effect of ensuring controllability, strong specificity and good resolution

Active Publication Date: 2018-03-09
YABAO PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In addition, specific impurities are specified in the current European Pharmacopoeia (EP 8.0), namely impurities A, B, C, D, E, F, G, although the crude dipyridamole produced after condensation with diethanolamine and the subsequent refining process The level of related substances can be monitored using this standard, but dichloride is an intermediate in the previous step of synthesizing dipyridamole, and the level of impurities directly determines the quality of the finished product and the difficulty of subsequent treatment.

Method used

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  • HPLC analysis method of key intermediate impurities for dipyridamole synthesis
  • HPLC analysis method of key intermediate impurities for dipyridamole synthesis
  • HPLC analysis method of key intermediate impurities for dipyridamole synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1 isocratic elution (comparative experiment)

[0036] Instruments and Conditions

[0037] High performance liquid chromatography: Agilent 1260

[0038] Chromatographic column: Octadecylsilane bonded silica gel column (Bondapak4.6×250mm, 5μm)

[0039] Flow rate: 1.0mL / min

[0040] Detection wavelength: 220nm

[0041] Column temperature: 25°C

[0042] Diluent: Chloroform-acetonitrile

[0043] Injection volume: 10μL

[0044] Mobile phase: acetonitrile: water = 92:8

[0045] Experimental procedure

[0046] Accurately weigh 50mg of dichloride, put it in a 50mL measuring bottle, add chloroform to dissolve, add acetonitrile to dilute to the volume, shake well, and use it as the test solution. Carry out high performance liquid chromatography analysis by above-mentioned condition, record chromatogram, the result sees attached figure 1, the retention times of trichloride and monochloride relative to dichloride are 0.33 and 2.47, respectively. Although the sep...

Embodiment 2

[0048] Instruments and Conditions

[0049] High performance liquid chromatography: Agilent 1260

[0050] Chromatographic column: phenylsilane bonded silica gel column (Kromasil 4.6×250mm, 5μm)

[0051] Flow rate: 1.0mL / min

[0052] Detection wavelength: 220nm

[0053] Column temperature: 25°C

[0054] Diluent: Chloroform-acetonitrile

[0055] Injection volume: 10μL

[0056] Mobile phase: mobile phase A: acetonitrile solution containing 0.1% phosphoric acid; mobile phase B: aqueous solution containing 0.1% phosphoric acid

[0057] Gradient elution:

[0058]

[0059] Experimental procedure

[0060] Step 1: Solution preparation

[0061] System suitability solution: Weigh the appropriate amount of tetrachloride, trichloride, dichloride and monochloride reference substance respectively, weigh them accurately, add appropriate amount of chloroform to dissolve, and dilute with acetonitrile to make about 0.5mg in each 1mL The mixed reference substance, as a system suitabili...

Embodiment 3

[0070] Instruments and Conditions

[0071] High performance liquid chromatography: Agilent 1260

[0072] Chromatographic column: phenylsilane bonded silica gel column (Kromasil 4.6×250mm, 5μm)

[0073] Flow rate: 1.1mL / min

[0074] Detection wavelength: 210nm

[0075] Column temperature: 22°C

[0076] Diluent: Chloroform-acetonitrile

[0077] Injection volume: 10μL

[0078] Mobile phase: mobile phase A: methanol solution containing 0.1% phosphoric acid; mobile phase B: aqueous solution containing 0.1% phosphoric acid

[0079] Gradient elution:

[0080]

[0081] Experimental procedure

[0082] Experimental procedure is with embodiment 2, and the result sees attached Figure 4 , the retention times of trichloride and monochloride relative to dichloride are 0.85 and 1.08 respectively, and the results of tetrachloride are shown in the appendix Figure 5 , the retention time relative to dichloride is about 0.72.

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Abstract

The invention discloses an HPLC analysis method of key intermediate impurities for dipyridamole synthesis. In the HPLC analysis method, a chromatographic column uses phenylsilane-bonded silica gel asa filler, an organic phase containing an acidic additive is used as a mobile phase A, an aqueous solution containing the acidic additive is used as a mobile phase B, a gradient elution method is adopted, the detection wavelength is 210-230 nm, and a key intermediate of the dipyridamole, namely 2,6-dichloro-4, 8-di(piperidin-1-yl)pyrimido[5,4-d] pyrimidine, and related impurities thereof are separated and determinated. The HPLC analysis method has the characteristics of a good degree of separation, simpleness, rapidity, high specificity and high sensitivity; by the HPLC analysis method, the quality of the key intermediate dichloride during the dipyridamole synthesis can be controlled, so that the post-treatment is simplified and the quality of a final product is guaranteed.

Description

technical field [0001] The invention relates to the field of medicinal chemistry and analysis, in particular to an HPLC analysis method for a key intermediate impurity synthesized by dipyridamole. Background technique [0002] Dipyridamole is an anti-platelet aggregation and coronary artery dilating drug. It prevents the formation of thrombus by inhibiting the cell absorption and metabolism of adenosine, increasing the concentration of cyclic adenosine monophosphate and other modes of action. Combined with aspirin It has the effect of synergistically dilating coronary vessels and reducing platelet aggregation. It is mainly used clinically to prevent the formation of cerebral thrombus and reduce the treatment of myocardial infarction. It is the main drug in the field of cardiovascular and cerebrovascular treatment. The chemical structure is as follows: [0003] [0004] Formula 2 is the synthesis route of dipyridamole and the impurity profile analysis spectrum during the s...

Claims

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Application Information

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IPC IPC(8): G01N30/02G01N30/06
CPCG01N30/02G01N30/06
Inventor 王羽何英翠
Owner YABAO PHARMA GRP CO LTD
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