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Detection method for related substances of Eltrombopag intermediate I

A technology for intermediate and impurity content, which can be used in measuring devices, instruments, scientific instruments, etc., can solve problems such as the analysis method of eltrombopag-free intermediates, and achieve convenient research on impurity transfer law and process parameter optimization, and moderate analysis time. , the effect of convenient operation

Active Publication Date: 2022-03-04
QILU PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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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 for related substances of Eltrombopag intermediate I
  • Detection method for related substances of Eltrombopag intermediate I
  • Detection method for related substances of Eltrombopag intermediate I

Examples

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 program

[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 amount of intermediate Ⅰ, impurity AL, impu...

Embodiment 2

[0094] Embodiment 2 intermediate II method verification

[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) Mobile phase A(%) Mobile phase B(%) 0 85 15 5 60 40 22 35 65 23 20 80 32 20 80 33 85 15 40 85 15

[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 o...

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; Cool down 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 is named as a method for detecting related substances of Eltrombopag intermediate I, and belongs to the technical field of drug analysis. The present invention respectively adopts chromatographic columns with phenyl and octadecylsilane bonded silica gel as fillers, uses phosphate buffer solution and acetonitrile or phosphate acetonitrile solution as mobile phase, adopts gradient elution mode, and establishes two high-efficiency The liquid phase analysis method can effectively determine Eltrombopag synthetic intermediate Ⅰ 2'-hydroxy-3'-amino-biphenyl-3-carboxylic acid and intermediate Ⅱ 2-(3,4-dimethyl-phenyl) ‑5‑methyl‑2,4‑dihydro‑pyrazole‑3‑one and the content of related impurities in the above-mentioned intermediates, the method has good specificity, high sensitivity, and convenient operation. effective guarantee. The invention also discloses a new 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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Patent Type & Authority Patents(China)
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 CO LTD
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