Impurity of erlotinib hydrochloride as well as preparation method and detection method thereof

A technology of erlotinib hydrochloride and impurities, which is applied to the process impurities of erlotinib hydrochloride and its preparation method and detection method, which can solve the problems affecting the quality of erlotinib hydrochloride products and adverse reactions.

Inactive Publication Date: 2015-03-25
CHENGDU SINO STRONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In view of the fact that the synthesis process reported in the literature is likely to lead to the production of etherification process impurities (compounds of formula I), which may affect the product quality of erlotinib hydrochloride, and may cause adverse reacti

Method used

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  • Impurity of erlotinib hydrochloride as well as preparation method and detection method thereof
  • Impurity of erlotinib hydrochloride as well as preparation method and detection method thereof
  • Impurity of erlotinib hydrochloride as well as preparation method and detection method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 Preparation of 4-methoxy-6,7-bis(2-methoxyethoxy)-quinazoline (Ⅰa)

[0030] Dissolve 1.0 g of 4-chloro-6,7-bis(2-methoxyethoxy)-quinazoline in 10 mL of methanol, and add 0.2 g of sodium methylate to the reaction solution in batches under stirring. After the addition, the stirring reaction was continued for 5 h, and the reaction was detected by TLC. After the reaction, the reaction solution was concentrated, the residue was dissolved in dichloromethane, washed with water and saturated brine in turn, the organic layer was dried, concentrated, the residue was slurried with ether, and filtered to obtain about 0.7 g of a white solid, yield: 71%. HRMS-ESI (m / z): 309.1445 (M +H + ); 1 H-NMR (400MHz, CDCl 3 ) δ = 8.59 (s, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 4.23~4.18 (m, 4H), 4.07 (s, 3H), 3.80~3.77 (m, 4H), 3.42 (s , 3H), 3.41 (s, 3H) ppm.

Embodiment 2

[0031] Example 2 Preparation of 4-methoxy-6,7-bis(2-methoxyethoxy)-quinazoline (Ⅰa)

[0032] Under ice-bath condition, dissolve 0.6g NaH in 10mL dry tetrahydrofuran, under stirring condition, dissolve 2.0 g 6,7-bis(2-methoxyethoxy)-4-quinazolinone (compound of formula III) The tetrahydrofuran solution was slowly dropped into the reaction solution, and after the drop was completed, it was raised to room temperature and stirred for 1 hour. Subsequently, 1.2 g of methyl iodide was slowly dropped into the reaction liquid, and stirred for 3 hours. After the reaction, the reaction solution was concentrated, and the residue was purified by column chromatography (eluent: ethyl acetate:petroleum ether = 1:1) to obtain about 0.8 g of a white solid with a yield of 41%.

Embodiment 3

[0033] Example 3 Application of Etherified Impurity Ⅰa of Erlotinib Hydrochloride as Impurity Control in High Performance Liquid Chromatography

[0034] It is used for the analysis of the impurity involved in the analysis of erlotinib hydrochloride bulk drug and its preparations. Chromatographic column used in high performance liquid chromatography: venusil XBP C8 4.6×150mm 5um, column temperature: 30°C, flow rate: 1.0ml / min, wavelength: 247nm, mobile phase: acetonitrile-0.05mol / L potassium dihydrogen phosphate solution (take Dissolve 6.80g of potassium dihydrogen phosphate in 1000ml of water, adjust the pH to 7.0 with phosphoric acid)=58:42.

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Abstract

The invention discloses a process impurity of erlotinib hydrochloride. The impurity is produced in a secondary reaction during the synthesis of erlotinib hydrochloride, due to the impurity, the quality of an erlotinib hydrochloride product is influenced and meanwhile an adverse reaction in the human body can be produced. The invention also provides a preparation method of the impurity and application of the impurity in detection of the erlotinib hydrochloride crude drugs and the quality of a preparation.

Description

technical field [0001] The invention relates to a process impurity of erlotinib hydrochloride, a preparation method and a detection method thereof, and belongs to the field of drug synthesis. Background technique [0002] Erlotinib Hydrochloride (Erlotinib Hydrochloride, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinolinamine hydrochloride, trade name: Tarceva, Tarceva) is a cancer treatment drug developed by OSI Pharmaceuticals in the United States, which belongs to the selective inhibitor of epidermal growth factor tyrosine kinase (EGFR-TK), which selectively blocks human epidermal growth factor receptor tyrosine kinase and reduces EGFR Its autophosphorylation, which leads to cell growth arrest and apoptosis, is mainly used for the treatment of non-small cell lung cancer. In 2005, the FDA approved the combination of erlotinib hydrochloride and gemcitabine for the treatment of advanced pancreatic cancer, becoming the first approved drug for the treatment of advanced p...

Claims

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Application Information

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IPC IPC(8): C07D239/88G01N30/02
CPCC07D239/88G01N30/02G01N2030/027
Inventor 张善军向显帅任宇高建
Owner CHENGDU SINO STRONG PHARMA
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