Preparation method of erlotinib hydrochloride impurities

A technology of nilotinib hydrochloride and impurities is applied in the field of 4-methyl, an important impurity in the preparation process, to achieve the effects of reducing side reactions, convenient operation and mild reaction conditions

Inactive Publication Date: 2017-06-30
HAINAN SIMCERE PHARMA CO LTD +1
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0004] Regarding the impurities of Nilotinib Hydrochloride (shown in formula II~V), the chemical names are respectively 4-methyl-N-[3-(4-ethyl-1H-imidazol-1-yl)-5-(three Fluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide (formula II), 4-methyl-N-[3-(2,4- Dimethyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide (formula III ), 4-methyl-N-[3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-yl Pyrimidin-2-yl)amino]benzamide (formula IV), 4-methyl-N-[3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide (formula V), there is no relevant literature report at present, and there is no report of its synthetic method, so it is necessary to develop these four impurities The preparation method is used for the quality control of nilotinib hydrochloride raw materials and preparations

Method used

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  • Preparation method of erlotinib hydrochloride impurities
  • Preparation method of erlotinib hydrochloride impurities
  • Preparation method of erlotinib hydrochloride impurities

Examples

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Effect test

Embodiment 1

[0026] Embodiment 1: the preparation of formula II compound

[0027]

[0028] The compound of formula VI (3.5 g), toluene (35 ml), and thionyl chloride (14 ml) were added into the reaction flask, and the temperature was raised to 80° C. for 5 h. The reaction solution was spin-dried, 3-(4-ethyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (2.0 g) and acetonitrile (70 ml) were added, and the temperature was raised to 80° C. for 7 h. Concentrate the reaction solution to obtain a black oil, which is separated and purified with a silica gel column. The eluent is dichloromethane:methanol=30:1. The product is collected and concentrated to obtain 2.9g of the compound of formula II. The molar yield is 69%, HPLC purity 98.40%. ESI-MS(m / z):543.9[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ: 10.62(s, 1H, CONH), 9.30(s, 1H, ArH), 9.18(s, 1H, NH), 8.70(s, 1H, ArH), 8.56(d, J=4.8Hz, 1H, ArH), 8.46(d, J=8.0Hz, 1H, ArH), 8.46(d, J=8.0Hz, 1H, ArH), 8.34(d, J=1.6Hz, 1H, ArH), 8.31(s, 1H , ArH)...

Embodiment 2

[0029] Embodiment 2: the preparation of formula III compound

[0030]

[0031]The compound of formula VI (3.5 g), tetrahydrofuran (25 ml), and oxalyl chloride (15 ml) were added into the reaction flask, and the temperature was raised to 60° C. for 6 h. Spin the reaction solution to dryness, add 3-(2,4-dimethyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (2.0g), toluene (100ml), and heat up to 70°C Reaction 6h. Concentrate the reaction solution to obtain a black solid, which is separated and purified with a silica gel column, the eluent is dichloromethane:methanol=50:1, the product is collected, and after concentration, 2.5g of the compound of formula III is obtained, with a molar yield of 59% , HPLC purity 99.03%. ESI-MS(m / z):543.9[M+H] + ; 1 H NMR (400MHz, CDCl 3 ):9.32(d,J=2.0Hz,1H,ArH),8.85(d,J=1.6Hz,1H,ArH),8.69(dd,J=4.8,1.6Hz,1H,ArH),8.66(s, 1H, CONH), 8.56(d, J=5.6Hz, 1H, ArH), 8.39(dt, J=8.0, 2.0, 1.6Hz, 1H, ArH), 8.10(d, J=1.6Hz, 1H, ArH) ,7.91(s,1H,ArH),7.6...

Embodiment 3

[0032] Embodiment 3: the preparation of formula IV compound

[0033]

[0034] The compound of formula VI (0.4g), acetonitrile (4ml) and thionyl chloride (1.8ml) were added into the reaction flask, and the temperature was raised to 80°C for 5h. The reaction solution was spin-dried, acetonitrile (10ml), 3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (0.2g) were added, and the temperature was raised to 60°C for 4h. Concentrate the reaction solution to obtain a yellow solid, which is separated and purified by a silica gel column, the eluent is dichloromethane:methanol=40:1, the product is collected, and after concentration, 0.27g of the compound of formula IV is obtained, with a molar yield of 61% , HPLC purity 99.49%. ESI-MS(m / z):529.9[M+H] + ; 1 H NMR (400MHz, CDCl 3 )δ: 9.32 (d, J = 1.6Hz, 1H, ArH), 8.85 (d, J = 1.6Hz, 1H, ArH), 8.68 (dd, J = 4.8, 1.6Hz, 1H, ArH), 8.62 (s ,1H,CONH),8.55(d,J=5.3Hz,1H,ArH),8.38(dt,J=8.0,1.9,1.9Hz,1H,ArH),8.10(t,J=1.8Hz,1H,ArH )...

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Abstract

The invention relates to a preparation method of important impurities in an erlotinib hydrochloride raw material or preparation technology. Compounds with formulas II to V are erlotinib hydrochloride impurities, and can be used as impurity reference substances to control the purity of theerlotinib hydrochloride raw material or the preparation.

Description

technical field [0001] The present invention relates to an important impurity in the nilotinib hydrochloride raw material or preparation process——4-methyl-N-[3-(4-ethyl-1H-imidazol-1-yl)-5-(trifluoromethyl )phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide (formula III), 4-methyl-N-[3-(2,4-dimethyl -1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide (formula IV), 4 -Methyl-N-[3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidine-2 -yl)amino]benzamide (formula V), 4-methyl-N-[3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4 -The preparation method of pyridin-3-ylpyrimidin-2-yl)amino]benzamide (formula VI). Background technique [0002] Nilotinib Hydrochloride (Nilotinib Hydrochloride) is a novel small molecule Bcr-Abl tyrosine kinase highly selective and potent oral inhibitor, mainly used for patients who are resistant to previous treatments (including imatinib) or have no Tolerated adu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 郭起黄俊杰廖明毅
Owner HAINAN SIMCERE PHARMA CO LTD
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