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Detection method of eltrombopag intermediate related substances and impurity reference substance used in method

A technology for the content of intermediates and impurities, applied in measuring devices, instruments, scientific instruments, etc., can solve the problems of Eltrombopag-free intermediate analysis methods, etc., and achieve convenient and specific research on impurity transfer rules and process parameter optimization , the effect of moderate analysis time

Active Publication Date: 2018-04-03
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there is no report on the analysis method of Eltrombopag intermediates in relevant literatures and patents, but comprehensive and systematic quality control from starting raw materials to final products, especially key intermediates in the synthesis process, is essential for Eltrombopag It has important guiding significance for quality research and improvement of synthesis process

Method used

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  • Detection method of eltrombopag intermediate related substances and impurity reference substance used in method
  • Detection method of eltrombopag intermediate related substances and impurity reference substance used in method
  • Detection method of eltrombopag intermediate related substances and impurity reference substance used in method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1 intermediate I method verification

[0066] 1. Chromatographic conditions

[0067] Instrument: Waters2695-2489-2998 high performance liquid chromatography - ultraviolet detector - diode array detector

[0068] Chromatographic column: use phenylsilane bonded silica gel [Xbridge Phenyl (4.6×250mm, 5μm)] as filler

[0069] Mobile phase A: 10mmol / L sodium dihydrogen phosphate (adjust the pH value to 3.5 with phosphoric acid)

[0070] Mobile phase B: 0.1% phosphoric acid in acetonitrile

[0071] gradient elution procedure

[0072] time (minutes)

Mobile phase A(%)

Mobile phase B(%)

0

87

13

3

87

13

26

64

36

38

40

60

39

87

13

45

87

13

[0073] Flow rate: 1.2ml / min; Column temperature: 50°C; Detection wavelength: 230nm; Injection volume: 10μl

[0074] 2. Method verification

[0075] (1) System suitability

[0076] Impurity localization solution: Take the appropriate ...

Embodiment 2

[0094] Embodiment 2 intermediate II method validation

[0095] 1. Chromatographic conditions

[0096] Instrument: Waters2695-2489-2998 high performance liquid chromatography - ultraviolet detector - diode array detector

[0097] Chromatographic column: use octadecylsilane bonded silica gel [Xbridge Shield RP-18 (4.6×150mm, 3.5μm)] as filler

[0098] Mobile phase A: 20mmol / L sodium dihydrogen phosphate (adjust the pH value to 3.0 with phosphoric acid)

[0099] Mobile Phase B: Acetonitrile

[0100] gradient elution procedure

[0101] time (min)

[0102] Flow rate: 1.0ml / min; Column temperature: 35°C; Sample chamber temperature: 4°C; Detection wavelength: 243nm; Injection volume: 10μl

[0103] 2. Method verification

[0104] (1) System suitability

[0105] Impurity localization solution: Take the appropriate amount of intermediate II, impurity SM1, impurity FJ, and impurity DH, weigh them accurately, put them in different measuring bottles, dissolve and dilute the...

Embodiment 3

[0123] The preparation of embodiment 3 impurity compound DH

[0124]

[0125] Dissolve 3.0g of compound SM1, 2.4g of compound ethyl acetoacetate, and 3.6g of sodium bisulfite in 12mL of ethanol and 12ml of purified water, stir and heat up to reflux, and react for 3 hours; after the reaction is complete, cool down to 40°C and stir for 1 hour; Lower the temperature to 25°C, keep warm and crystallize for 5 hours; filter with suction, evaporate the filtrate to dryness, and separate by column chromatography to obtain 1.1 g of impurity DH.

[0126] ESI(+): m / z 231.20;

[0127] [M+1] + ; 1 H NMR: (400MHz,DMSO-d6)δ=7.40(d,1H),7.39(m,1H),7.13(d,1H),5.63(s,1H),4.10(d,2H),2.22(s ,3H), 2.19(s,3H), 2.12(s,3H), 1.31(m,3H).

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Abstract

The invention discloses a detection method of eltrombopag intermediate related substances and an impurity reference substance used in the method and belongs to the technical field of pharmaceutical analysis. A chromatographic column taking phenyl and octadecyl silane bonded silica gel as filler is adopted, a phosphate buffer solution and an acetonitrile or phosphate-acetonitrile solution are adopted as mobile phases, a gradient elution manner is adopted, two established HPLC (high performance liquid chromatography) analysis methods can effectively determine the content of eltrombopag intermediate I 2'-hydroxyl-3'-amino-diphenyl-3-carboxylic acid and intermediate II 2-(3,4-dimethyl-phenyl)-5-methyl-2,4-dihydro-pyrazole-3-one as well as intermediate related impurities, the method is good inspecificity, high in sensitivity and convenient to operate, and quality control of a final eltrombopag product is effectively guaranteed. The invention also discloses a novel impurity reference substance compound.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical analysis, and in particular relates to a method for the determination of intermediate I 2'-hydroxyl-3'-amino-biphenyl-3-carboxylic acid and intermediate II 2-(3,4) used in the synthesis of Eltrombopag - Pharmaceutical analysis method for content of dimethyl-phenyl)-5-methyl-2,4-dihydro-pyrazol-3-one related impurities. [0002] The present invention also relates to a new impurity reference substance compound DH used in the analysis method of Eltrombopag intermediate II. Background technique [0003] Eltrombopag, chemical name 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro- 4H-pyrazole-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid diethanolamine, molecular formula is C 25 h 22 N 4 o 4 2C 2 h 7 NO, the molecular weight is 564.63, its structural formula is as follows: [0004] [0005] Eltrombopag is an oral thrombopoietin drug, the compound can interact w...

Claims

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Application Information

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IPC IPC(8): G01N30/06G01N30/74G01N30/86
CPCG01N30/06G01N30/74G01N30/8634
Inventor 马超李书彬管凯林周英兰刘振杜永辉范传文
Owner QILU PHARMA
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