发明名称 |
Process for the manufacture of (<i>E</i>)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors |
摘要 |
The present invention is directed to an efficient process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form of formula I;
wherein R1 and R2 independently denote C1-3-alkyl groups and X− denotes an acid anion, such as the chloride, bromide, tosylate, mesylate or trifluoroacetate anion, with high quality, and a process for synthesis of EGFR tyrosine kinase inhibitors with heterocyclic quinazoline, quinoline or pyrimidopyrimidine core structure, using the acid addition salt I and activated derivatives thereof as intermediates. |
申请公布号 |
US9242965(B2) |
申请公布日期 |
2016.01.26 |
申请号 |
US201414576849 |
申请日期 |
2014.12.19 |
申请人 |
Boehringer Ingelheim International GmbH |
发明人 |
Zheng Juncheng;Deng Da;Lv Guanghua;Yan Jun;Brandenburg Joerg;Kroeber Jutta;Scholz Ulrich |
分类号 |
C07C227/00;C07D405/00;C07C221/00;C07D405/04;C07C227/18;C07C227/16;C07C227/10 |
主分类号 |
C07C227/00 |
代理机构 |
|
代理人 |
Morris Michael P.;Stempel Alan R. |
主权项 |
1. A process for the manufacture of (E)-4-N,N-di-(C1-3)-alkylamino crotonic acid in HX salt form of formula I wherein R1 and R2 independently denote C1-3-alkyl groups and X− denotes an acid anion, comprising the following synthesis steps: a) step 1: wherein R1, R2 and R3 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes an acid selected from HCl, HBr, MeSO3H, p-CH3C6H4SO3H (p-toluenesulfonic acid) and CF3CO2H, the base denotes a strong base, and solvent denotes water, a water miscible organic solvent, and the mixtures thereof, and b) step 2: wherein R1 and R2 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes an acid, and solvent denotes a suitable solvent. |
地址 |
Ingelheim am Rhein DE |