PROCESS FOR THE MANUFACTURE OF (E)-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 C_1-3-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.