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Method for preparing intermediate of Afatinib

A compound and molar ratio technology, applied in the field of preparation of afatinib intermediates, can solve the problems of unsuitable industrial production, complex operation, high cost, etc., and achieve the effect of less raw material consumption, simple operation and low cost

Active Publication Date: 2017-09-29
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to overcome the defects such as low yield, complex operation, difficult solvent recovery, high cost, and inapplicability to industrialized production in the preparation method of the existing afatinib intermediate, and provides a The preparation method of Afatinib intermediate

Method used

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  • Method for preparing intermediate of Afatinib
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  • Method for preparing intermediate of Afatinib

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Add 10 g of 6-nitro-4-[(3-chloro-4-fluoro-phenyl) amino]-7-chloroquinazoline and 0.57 g of sodium methylsulfinate into a three-necked flask equipped with a thermometer and a reflux condenser. g. (S)-3-hydroxytetrahydrofuran 5.2g, potassium carbonate 5.9g, DMF 50ml, react at 120°C for 3h. The reaction solution was added to 150 ml of water, filtered with suction, washed with water, and dried to obtain 7.0 g of black solid 9, with a yield of 61.2%. mp 243.1-249.9°C.

Embodiment 2

[0028] Add 20.0 g of 6-nitro-4-[(3-chloro-4-fluoro-phenyl)amino]-7-chloroquinazoline and sodium methylsulfinate into a three-necked flask equipped with a thermometer and a reflux condenser 1.27g, (S)-3-hydroxytetrahydrofuran 10.3g, potassium tert-butoxide 12.7g, DMF 100ml, react at 80°C for 3h. The reaction solution was added to 300ml of water, suction filtered, washed with water, and dried to obtain 21.3 g of yellow solid 9, with a yield of 93%. mp 245.2-247.9°C.

Embodiment 3

[0030] Add 20 g of 6-nitro-4-[(3-chloro-4-fluoro-phenyl)amino]-7-chloroquinazoline and 1.27 g of sodium methylsulfinate into a three-necked flask equipped with a thermometer and a reflux condenser. g. (S)-3-hydroxytetrahydrofuran 10.3g, potassium tert-butoxide 12.7g, DMF 100ml, react at 60°C for 12h. The reaction solution was added to 300ml of water, filtered with suction, washed with water, and dried to obtain 18.9 g of khaki solid 9, with a yield of 82.7%. mp 244.5-249.2°C.

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Abstract

The invention discloses a method for preparing an intermediate of Afatinib. The method comprises the following step: subjecting a compound represented by a formula 7 shown in the description, sodium methanesulfonate and (S)-3-hydroxyl tetrahydrofuran to a reaction as follows in an organic solvent in the presence of alkali, thereby preparing a compound represented by a formula 9 shown in the description. The method disclosed by the invention is high in yield, simple in operation and low in cost and is more applicable to industrial production.

Description

technical field [0001] The invention relates to a preparation method of an afatinib intermediate. Background technique [0002] Afatinib was developed by Boehringer Ingelheim in Germany and was approved by the US FDA on July 12, 2013. It is an irreversible EGFR-HER-2 dual tyrosine kinase receptor inhibitor and is clinically used for EGFR First-line treatment of metastatic non-small-cell lung cancer (NSCLC) patients with exon 19 deletion and exon 21 substitution mutations. The chemical name of afatinib is (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furyl]oxy] -6-quinazolinyl]-4-(dimethylamino)-2-butenamide, as shown in formula 1. [0003] [0004] Boehringer Ingelheim's original research patent WO2007085638 reports the preparation method of intermediate 9: intermediate 6-nitro-4-[(3-chloro-4-fluorophenyl-amino)-7-chloroquinazoline 7 in DMF with benzene Sodium sulfinate reacts to obtain 6-nitro-4-[(3-chloro-4-fluoro-phenyl) amino]-7-benzenesulfonylqu...

Claims

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Application Information

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IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 张福利陈灵灵吴泰志饶程皓李忠黄逸文曾宪国彭莉
Owner SHANGHAI INST OF PHARMA IND
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