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Preparation method of erlotinib intermediate

An erlotinib and intermediate technology, applied in the field of organic synthesis, can solve the problems of harsh conditions and high cost, and achieve the effects of less impurities, low production cost and high purity

Active Publication Date: 2016-05-11
CHONGQING WEIPENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, in this process, oxyalkylation needs to be refluxed in DMSO, and the conditions are too harsh; palladium-carbon catalytic hydrogenation is used for nitration reduction, and the cost is high

Method used

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  • Preparation method of erlotinib intermediate
  • Preparation method of erlotinib intermediate
  • Preparation method of erlotinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1 prepares 6,7,-two (2-methoxyethoxy) quinazolin-4-ones

[0041] Follow the steps below:

[0042] 1. Add 150g (1eq) of vanillin and 1500ml of chloroform into a 3L three-necked flask, stir, dissolve, and cool to 0-10°C in an ice-water bath; add 167g (1eq) of anhydrous aluminum trichloride at one time while stirring; Control the temperature at 0-20°C, slowly add 235g (3eq) of pyridine dropwise, and stir at room temperature for 30min after the dropwise addition; reflux reaction overnight, cool down to room temperature with a water bath, add dropwise a mixture of 250ml of water and 100ml of concentrated hydrochloric acid, and cool down Stir at room temperature until the solid is completely dissolved, and the measured pH should be 2 to 3; after dissolving, let stand to separate layers, extract the water layer with chloroform, and combine the chloroform layer; wash the chloroform layer with water, and combine the water layer; the water layer is washed with ethyl ac...

Embodiment 2

[0049] Embodiment 2 prepares 6,7,-two (2-methoxyethoxy) quinazolin-4-ones

[0050] Follow the steps below:

[0051] 1. Add 150g (1eq) vanillin and 1500ml dichloromethane into a 3L three-necked flask, stir, dissolve, and cool to 0-10°C in an ice-water bath; add 334g (2eq) anhydrous trichloride at one time while stirring Aluminum; temperature control at 0-20°C, slowly add 392g (5eq) pyridine dropwise, stir at room temperature for 30min after dropwise addition; reflux reaction for 24h, cool down to room temperature with a water bath, dropwise add a mixture of 250ml water and 100ml concentrated hydrochloric acid dropwise , lower the temperature to room temperature and stir until the solid is completely dissolved, and the measured pH should be 2 to 3; after dissolving, let stand and separate the layers, extract the water layer with dichloromethane, and combine the dichloromethane layer; wash the dichloromethane layer with water, and combine Aqueous layer; the aqueous layer was ext...

Embodiment 3

[0058] Embodiment 3 prepares 6,7,-two (2-methoxyethoxy) quinazolin-4-ones

[0059] Follow the steps below:

[0060] 1. Add 150g (1eq) vanillin and 1500ml chloroform into a 3L three-necked flask, stir, dissolve, and cool to 0-10°C in an ice-water bath; add 234g (1.4eq) anhydrous aluminum trichloride at one time while stirring ;Temperature control at 0-20°C, slowly add 250.6g (3.2eq) pyridine dropwise, after the dropwise addition, stir at room temperature for 30min; reflux reaction overnight, cool down to room temperature with a water bath, dropwise add a mixture of 250ml water and 100ml concentrated hydrochloric acid After finishing, cool down to room temperature and stir until the solid matter dissolves completely, and the measured pH should be 2 to 3; after dissolving, let it stand for stratification, extract the water layer with chloroform, and combine the chloroform layer; wash the chloroform layer with water, and combine the water layer; the water layer Extract with ethyl...

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Abstract

The invention relates to a preparation method of an erlotinib intermediate. The method concretely comprises the following steps: 1, dissolving vanillin in an organic solvent I, adding aluminum trichloride, adding pyridine in a dropwise manner, and reacting to obtain ELTA; 2, dissolving the ELTA in an organic solvent II, adding 2-chloroethylmethyl ether, potassium carbonate and a phase transfer catalyst, and reacting to obtain ELTB; 3, adding the ELTB to water, adding an alkali and potassium permanganate, and reacting to obtain ELTC; 4, adding concentrated sulfuric acid to methanol in a dropwise manner, adding the ELTC to the above reaction system, and reacting to obtain ELTD; 5, adding concentrated sulfuric acid to concentrated nitric acid in a dropwise manner, dissolving the ELTD in an organic solvent IV, adding a prepared mixed acid to the reaction system, and reacting to obtain ELTE; 6, adding the ELTE, iron powder and ammonium chloride to an organic solvent V, adding concentrated hydrochloric acid in a dropwise manner, and reacting to obtain ELTF; and 7, adding the ELTF, trimethyl orthoformate and ammonium acetate to an organic solvent VI, and reacting to obtain the erlotinib intermediate.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of 6,7,-bis(2-methoxyethoxy)quinazolin-4-one, an important intermediate of erlotinib. Background technique [0002] Erlotinib is an anticancer drug, and 6,7,-bis(2-methoxyethoxy)quinazolin-4-one is an important intermediate for the synthesis of erlotinib. [0003] U.S. Pfizer and OSI first reported the following synthetic method in WO9630347A1 in 1995: [0004] [0005] The disadvantage of this method is the use of expensive platinum catalyst, H 2 Medium pressurization reaction, ring closure reaction temperature is high, these shortcomings are all unfavorable for industrialized production. [0006] Japan Ube Industries Co., Ltd. reported the following synthesis method in CN1860105A1 in 2004: [0007] [0008] The difference between this patent and the patent published by Pfizer lies in the use of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate, methyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/88
CPCC07D239/88
Inventor 颜伟伟任彦荣刘泽燕韩公超
Owner CHONGQING WEIPENG PHARMA
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