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 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.

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 Iwherein 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, andb) 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.