METHOD FOR PREPARING 1-(4-(4-(3,4-DICHLORO-2-FLUOROPHENYLAMINO)-7-METHOXY QUINAZOLIN-6-YLOXY)PIPERIDIN-1-YL)PROP-2-EN-1-ONE HYDROCHLORIDE AND INTERMEDIATES USED THEREIN
BANG, KEUK CHAN,방극찬,MOON, YOUNG HO,문영호,CHANG, YOUNG KIL,장영길
申请号：
KR1020110101422
公开号：
KR1020130037079A
申请日:
2011.10.05
申请国别(地区):
KR
年份:
2013
代理人:
摘要：
PURPOSE: A method for preparing high yield and high purity 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxy quinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one hydrochloride is provided to cheaply and effectively prepare the compound. CONSTITUTION: A method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxy quinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one hydrochloride of chemical formula 1 comprises the following steps: a step of reacting a compound of chemical formula 8 with a compound of chemical formula 10 under the presence of an organic base and a halogenating agent to prepare a compound of chemical formula 6； a step of reacting the compound of chemical formula 6 in a polar protic solvent to prepare a compound of chemical formula 5； a step of nucleophilic substitution of the compound of chemical formula 5 with a compound of chemical formula 9 in an inert polar protic solvent under the presence of a base to prepare a compound of chemical formula 4； a step of deprotecting the compound of chemical formula 4 in an inert solvent using acid under the presence of an inert solvent to prepare a compound of chemical formula 3； a step of acrylation of the compound of chemical formula 3 under the presence of a base to prepare a compound of chemical formula 2； and a step of reacting the compound of chemical formula 2 with hydrochloric acid.본 발명은 상피세포 성장인자 수용체의 과발현에 의해 유발되는 암세포의 성장 및 티로신 키나아제 돌연변이에 의해 유발되는 약물의 내성을 선택적이고 효과적으로 억제할 수 있는 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온 염산염을 제조하는 데 유용한 개선된 제조방법 및 이에 사용되는 중간체에 관한 것이다.
